Bio


Dr. Kari Nadeau is one of the nation’s foremost experts in adult and pediatric allergy and asthma. She is the Director of the Sean N. Parker Center for Allergy and Asthma Research at Stanford University, Section Chief of Allergy and Asthma at the Stanford School of Medicine, and an endowed professor under the Naddisy Family Foundation. 

Dr. Nadeau received her MD and PhD from Harvard Medical School, completed a residency in pediatrics at Boston Children’s Hospital and a clinical fellowship in asthma and immunology at Stanford. After completing her residency, she spent 5 years in the biopharmaceutical industry, where she was instrumental in obtaining FDA approval for two biologics in the fields of autoimmunity and oncology, before starting her fellowship at Stanford.

Dr. Nadeau has received honors and awards from the American Academy of Allergy, Asthma & Immunology; the American Lung Association; the Clinical Immunological Society; Food Allergy Research & Education (FARE); and the NIH. She has also been recognized with the U.S. Environmental Protection Agency’s STAR Grant Award. Dr. Nadeau has served as a reviewer for NIH Study Sections, and a member of the American Lung Association Medical Board, CA. She serves on the Environmental Health Policy committee for the American Thoracic Society and is a Fellow in the American Academy of Allergy, Asthma and Immunology as well as a member of ASCI (American Society of Clinical Investigation).

She has authored or co-authored more than 100 original papers. Her research focuses on understanding the factors responsible for the increased prevalence of allergies and asthma in the population, improving diagnostics, and understanding the immunological mechanisms underlying these diseases. She was the first to successfully desensitize individuals to more than one allergy at a time using multi-allergen oral immunotherapy. She continues to push forward with innovative clinical research using novel antibodies, peptide vaccines, and nanoparticles in order to provide safe and effective therapeutic options for those with allergies and asthma.

Clinical Focus


  • Allergy and Immunology
  • Adult and Pediatric Asthma, Allergy, and Immunology

Academic Appointments


Administrative Appointments


  • Volunteer Clinical Instructor, General Pediatrics (2003 - 2005)
  • Instructor, Allergy and Immunology (2006 - 2007)
  • Instructor, ENT (2007 - 2008)
  • Assistant Professor, Affiliate appointment in Otolaryngology (2007 - 2011)
  • Assistant Professor, Pediatrics (2007 - 2011)
  • Assistant Program Director, Allergy & Immunology Fellowship Program (2007 - 2011)
  • Medical Director, Allergy & Immunology Clinics (2007 - 2011)
  • Faculty Member, Stanford Institute of Immunity, Transplantation and Infectious Disease (2007 - Present)
  • Faculty Member, Multidisciplinary Program in Immunology (2007 - Present)
  • Associate Professor, Affiliate appointment in Otolaryngology (2011 - Present)
  • Associate Professor, Pediatrics (2011 - Present)
  • Director, Sean N. Parker Center for Allergy Research at Stanford University (2014 - Present)
  • Section Chief, Allergy and Asthma at the Stanford School of Medicine (2016 - Present)

Honors & Awards


  • Pediatric Research Award, CHRP (July 2007-July 2008)
  • Parker B Francis Award, Francis Foundation (July 2006-July 2009)
  • Mary Hewitt Loveless Award, Loveless Foundation (July 2006-July 2009)
  • Stanford Free Clinics Teaching Award, Stanford Medical School (June 2007)
  • National Junior Faculty Award, American Academy of Asthma, Allergy and Immunology (2007)
  • Speaker Award, La Entrada Inspirational Speaker Series (2007)
  • Fellow, American Academy of Asthma, Allergy and Immunology (2008-present)
  • National Junior Faculty Award, American Lung Association (2009)
  • Junior Faculty Award, Clinical Immunological Society (2010)

Boards, Advisory Committees, Professional Organizations


  • Faculty Fellow, Stanford Center for Innovation in Global Health (2015-Present) (2015 - Present)

Professional Education


  • Fellowship:Stanford University Medical Center (2006) CA
  • Residency:Children's Hospital Boston (1997) MA
  • Residency:Stanford University Medical Center (2004) CA
  • Internship:Children's Hospital Boston (1996) MA
  • Medical Education:Harvard Medical School (1995) MA
  • Board Certification: Allergy and Immunology, American Board of Allergy and Immunology (2007)
  • PhD, Harvard Medical School, Biochemistry and Immunology (1995)
  • B.S., Haverford College, Biology (1988)

Community and International Work


  • Volunteer Clinical Faculty, Menlo Park VA

    Topic

    Clinic for underserved

    Partnering Organization(s)

    Stanford/Menlo Park VA

    Populations Served

    underserved

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    Yes

Current Research and Scholarly Interests


The focus of our clinical research is to find safe and effective treatments for allergy and asthma. In 2014, we demonstrated that oral immunotherapy can simultaneously and successfully achieve desensitization for multiple food allergens (up to 5) and that adjunctive omalizumab therapy, by blocking free IgE, facilitates and decreases time to desensitization (Begin et al, 2014). Additional immunotherapy trials with adjunctive omalizumab (peanuts and milk) have supported these findings (Wood et al, 2016; MacGinnitie et al, 2017). The data from these clinical trials have provided initial evidence for the safety and feasibility of oral immunotherapy for food allergy and have paved the way for further innovative research in the field. Currently, we have in progress a number of novel immunotherapy trials for food allergy and asthma. Some of these include the use of skin patches for delivering allergens, the use of novel immunoglobulins (anti-IL-33, anti-IL-23), and DNA vaccines. On analyzing data obtained from these clinical studies, we hope to better understand the mechanisms that underlie allergy and asthma.

The focus of our basic research is to understand the characteristics of the allergens that mediate clinical reactions, the role of the environment and genetics in increasing risk of allergies and asthma, and the molecular, cellular, and genetic differences between those with allergies and asthma and those who are immune tolerant or those who achieve desensitization through immunotherapy. Our multifood allergen immunotherapy studies have enabled determination of associations and cross-reactivities between different food allergens and have further assisted us with epitope mapping, identification, and characterization of allergenic components of foods that induce clinical reactivity (Zhang et al, 2016; Zhang et al, 2016; Andorf et al, 2017). Data from these studies may, in the future, enable therapeutic targets for food allergies.

We are particularly interested in the role of T cells in immune tolerance. Using state-of-the-art techniques, such as allergen-specific T-cell sorting and single-cell gene expression, we have successfully demonstrated that it is possible to monitor patients undergoing immunotherapy by high dimensional immunophenotyping of T cells and predict the success of future treatments (Ryan et al, 2016). These findings can be used to impact patient management in real time. Our group has also shown that environmental factors such as exposure to small particulate matter from diesel and industrial fumes impair regulatory T cell function in asthma (Nadeau et al, 2010) and that air purifiers that reduce indoor fine particulate matter (<2.5 micrometer diameter) significantly improves nasal symptoms in children with allergic rhinitis (Park et al, 2016). Data from our immunotherapy trials indicate that epigenetic modifications may play an important role in regulating allergic disease and asthma (Syed et al, 2014) and may serve as useful biomarkers for diagnosis and prognosis.

As we move forward, the focus of the Center is to translate our understanding of the basic science underlying allergic disease and asthma to enable novel and innovative clinical studies and induce tolerance through immunotherapy.

Clinical Trials


  • Efficacy and Safety of Several Doses of Viaskin Peanut in Adults and Children With Peanut Allergy Recruiting

    The objectives of this dose-finding study for the treatment of peanut allergy are: - To determine the efficacy of 3 doses of Viaskin Peanut (50 mcg ,100 mcg and 250 mcg peanut protein per patch) to significantly desensitize peanut-allergic subjects to peanut after 12 months of treatment. - To evaluate the safety of a long-term treatment with Viaskin Peanut.

    View full details

  • Peanut Reactivity Reduced by Oral Tolerance in an Anti-IgE Clinical Trial Recruiting

    The investigators will perform a double blind, placebo controlled clinical trial with Xolair (omalizumab) at four centers to safely and rapidly desensitize patients with severe peanut allergy. The investigators will determine if pretreatment with anti-IgE mAb (Xolair/omalizumab) can greatly reduce allergic reactions and allow for faster and safer desensitization.

    View full details

  • Safety Study of Viaskin Peanut to Treat Peanut Allergy Recruiting

    This study evaluates the safety of Viaskin Peanut 250 mcg in the treatment of peanut allergy in children from 4 to 11 years of age. Subjects will receive either Viaskin Peanut 250 mcg or a placebo for a period of 6 months, after which all subjects will be receiving the active treatment up to a period of 3 years under active treatment.

    View full details

  • Understanding and Diagnosing Allergic Disease in Twins Recruiting

    The purpose of this study is to gain better understanding of how the immune system works in twins with and without allergic disease. Healthy volunteers are not specifically targeted. Healthy non-allergic study participants may be found through the course of evaluation for the presence of allergies.

    View full details

  • Efficacy and Safety of Viaskin Milk in Children With IgE-Mediated Cow's Milk Allergy Not Recruiting

    The objectives of this study are to evaluate the safety and efficacy of Viaskin Milk after 12 months of epicutaneous immunotherapy (EPIT) treatment, for desensitizing IgE-mediated cow's milk allergic children and to assess the long-term safety and treatment efffect of up to 48 months of treatment with Viaskin Milk

    Stanford is currently not accepting patients for this trial. For more information, please contact Kari Nadeau, 650-724-0293.

    View full details

  • Omalizumab With Oral Food Immunotherapy With Food Allergies Open Label Safety Study in a Single Center Not Recruiting

    The long-term goal of the investigators study is to develop a better and safer treatment for, and to potentially cure patients with single or multiple food allergies. The investigators hypothesize that the application of this protocol will allow patients with severe and single or multiple food allergies to be safely and rapidly desensitized.

    Stanford is currently not accepting patients for this trial. For more information, please contact Tina Dominguez, PA, safar_inquiry@stanford.edu .

    View full details

  • Placebo-Controlled Study to Investigate ANB020 Activity in Adult Patients With Peanut Allergy Not Recruiting

    The purpose of this study is to determine ANB020 safety, tolerability and activity in adult patients with peanut allergy.

    Stanford is currently not accepting patients for this trial.

    View full details

  • Study Using Xolair in Rush Multi Oral Immunotherapy in Multi Food Allergic Patients Not Recruiting

    This is a pilot randomized, double-blind, placebo controlled study which will be conducted at a single center. All participants will receive oral immunotherapy for their specific food allergies (limited to 5 of those food allergens in IND 14831). In a 3:1 ratio, 36* participants will receive Xolair for 16 weeks while 12* will receive corresponding placebo instead of Xolair. 12 controls will be enrolled who will receive no OIT and no Xolair. These 12 controls are not part of the randomization. The arms that are randomized are 48*.

    Stanford is currently not accepting patients for this trial.

    View full details

  • The Peanut Oral Immunotherapy Study: Safety, Efficacy and Discovery Not Recruiting

    Determine whether peanut oral immunotherapy (OIT) induces clinical tolerance as assessed after the initial 3 month avoidance period Secondary Objectives: - Identify the basic immune mechanisms which can explain the differences in the effects of OIT in desensitized vs. tolerant individuals. - Determine whether immune monitoring measurements reflecting underlying mechanisms during OIT can be used to predict responses to OIT in individual subjects and, ultimately, to improve the safety and efficacy outcomes in peanut OIT protocols.

    Stanford is currently not accepting patients for this trial.

    View full details

2017-18 Courses


Graduate and Fellowship Programs


All Publications


  • Biologic Therapies for Immunoglobulin E-mediated Food Allergy and Eosinophilic Esophagitis IMMUNOLOGY AND ALLERGY CLINICS OF NORTH AMERICA Otani, I. M., Nadeau, K. C. 2017; 37 (2): 369-?

    Abstract

    Immunoglobulin (Ig) E-mediated food allergy and eosinophilic esophagitis (EoE) are chronic, allergen-mediated disorders characterized by an aberrant TH2 immune response. The development and investigation of biologics for the treatment of IgE-mediated food allergy and eosinophilic esophagitis have provided further insight into the pathophysiology and management of these disorders. This article provides an overview of biologic therapies that are being investigated or have potential as treatments for IgE-mediated food allergy and eosinophilic esophagitis. Identification of EoE phenotypes that are responsive to biologics and investigation of biologics combined with other therapies may help elucidate a role for biologics in EoE.

    View details for DOI 10.1016/j.iac.2017.01.010

    View details for Web of Science ID 000400321000013

    View details for PubMedID 28366483

  • Traffic-Related Air Pollution and Telomere Length in Children and Adolescents Living in Fresno, CA: A Pilot Study. Journal of occupational and environmental medicine Lee, E. Y., Lin, J., Noth, E. M., Hammond, S. K., Nadeau, K. C., Eisen, E. A., Balmes, J. R. 2017; 59 (5): 446-452

    Abstract

    The main objective of this pilot study was to gather preliminary information about how telomere length (TL) varies in relation to exposure to polycyclic aromatic hydrocarbons (PAHs) in children living in a highly polluted city.We conducted a cross-sectional study of children living in Fresno, California (n = 14). Subjects with and without asthma were selected based on their annual average PAH level in the 12-months prior to their blood draw. We measured relative telomere length from peripheral blood mononuclear cells (PBMC).We found an inverse linear relationship between average PAH level and TL (R = 0.69), as well as between age and TL (R = 0.21). Asthmatics had shorter mean telomere length than non-asthmatics (TLasthmatic = 1.13, TLnon-asthmatic = 1.29).These preliminary findings suggest that exposure to ambient PAH may play a role in telomere shortening.Become familiar with previous evidence suggesting that telomere length may be a biomarker of air pollution-induced cytotoxicity.Summarize the new findings on the association between polycyclic aromatic hydrocarbon (PAH) exposure and telomere length in adolescents, including those with asthma.Discuss the implications for recommendations and policies to mitigate the health and respiratory effects of traffic-related air pollution.

    View details for DOI 10.1097/JOM.0000000000000996

    View details for PubMedID 28486341

  • Small-Magnitude Effect Sizes in Epigenetic End Points are Important in Children's Environmental Health Studies: The Children's Environmental Health and Disease Prevention Research Center's Epigenetics Working Group ENVIRONMENTAL HEALTH PERSPECTIVES Breton, C. V., Marsit, C. J., Faustman, E., Nadeau, K., Goodrich, J. M., Dolinoy, D. C., Herbstman, J., Holland, N., LaSalle, J. M., Schmidt, R., Yousefi, P., Perera, F., Joubert, B. R., Wiemels, J., Taylor, M., Yang, I. V., Chen, R., Hew, K. M., Freeland, D. M., Miller, R., Murphy, S. K. 2017; 125 (4): 511-526

    Abstract

    Characterization of the epigenome is a primary interest for children's environmental health researchers studying the environmental influences on human populations, particularly those studying the role of pregnancy and early-life exposures on later-in-life health outcomes.Our objective was to consider the state of the science in environmental epigenetics research and to focus on DNA methylation and the collective observations of many studies being conducted within the Children's Environmental Health and Disease Prevention Research Centers, as they relate to the Developmental Origins of Health and Disease (DOHaD) hypothesis.We address the current laboratory and statistical tools available for epigenetic analyses, discuss methods for validation and interpretation of findings, particularly when magnitudes of effect are small, question the functional relevance of findings, and discuss the future for environmental epigenetics research.A common finding in environmental epigenetic studies is the small-magnitude epigenetic effect sizes that result from such exposures. Although it is reasonable and necessary that we question the relevance of such small effects, we present examples in which small effects persist and have been replicated across populations and across time. We encourage a critical discourse on the interpretation of such small changes and further research on their functional relevance for children's health.The dynamic nature of the epigenome will require an emphasis on future longitudinal studies in which the epigenome is profiled over time, over changing environmental exposures, and over generations to better understand the multiple ways in which the epigenome may respond to environmental stimuli.

    View details for DOI 10.1289/EHP595

    View details for Web of Science ID 000397904400011

    View details for PubMedID 28362264

  • Association of Clinical Reactivity with Sensitization to Allergen Components in Multifood-Allergic Children. journal of allergy and clinical immunology. In practice Andorf, S., Borres, M. P., Block, W., Tupa, D., Bollyky, J. B., Sampath, V., Elizur, A., Lidholm, J., Jones, J. E., Galli, S. J., Chinthrajah, R. S., Nadeau, K. C. 2017

    Abstract

    Thirty percent of children with food allergies have multiple simultaneous allergies; however, the features of these multiple allergies are not well characterized serologically or clinically.We comprehensively evaluated 60 multifood-allergic patients by measuring serum IgE to key allergen components, evaluating clinical histories and medication use, performing skin tests, and conducting double-blind, placebo-controlled food challenges (DBPCFCs).Sixty participants with multiple food allergies were characterized by clinical history, DBPCFCs, total IgE, specific IgE, and component-resolved diagnostics (IgE and IgG4) data. The food allergens tested were almond, egg, milk, sesame, peanut, pecan, walnut, hazelnut, cashew, pistachio, soy, and wheat.Our data demonstrate that of the reactions observed during a graded DBPCFC, gastrointestinal reactions occurred more often in boys than in girls, as well as in individuals with high levels of IgE to 2S albumins from cashew, walnut, and hazelnut. Certain food allergies often occurred concomitantly in individuals (ie, cashew/pistachio and walnut/pecan/hazelnut). IgE testing to components further corroborated serological relationships between and among these clustered food allergies.Associations of certain food allergies were shown by DBPCFC outcomes as well as by correlations in IgE reactivity to structurally related food allergen components. Each of these criteria independently demonstrated a significant association between allergies to cashew and pistachio, as well as among allergies to walnut, pecan, and hazelnut.

    View details for DOI 10.1016/j.jaip.2017.01.016

    View details for PubMedID 28351786

  • Assessing basophil activation by using flow cytometry and mass cytometry in blood stored 24 hours before analysis JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Mukai, K., Gaudenzio, N., Gupta, S., Vivanco, N., Bendall, S. C., Maecker, H. T., Chinthrajah, R. S., Tsai, M., Nadeau, K. C., Galli, S. J. 2017; 139 (3): 889-?
  • Omalizumab facilitates rapid oral desensitization for peanut allergy JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY MacGinnitie, A. J., Rachid, R., Gragg, H., Little, S. V., Lakin, P., Cianferoni, A., Heimall, J., Makhija, M., Robison, R., Chinthrajah, R. S., Lee, J., LeBovidge, J., Dominguez, T., Rooney, C., Lewis, M. O., Koss, J., Burke-Roberts, E., Chin, K., Logvinenko, T., Pongracic, J. A., Umetsu, D. T., Spergel, J., Nadeau, K. C., Schneider, L. C. 2017; 139 (3): 873-?
  • Preservation of epithelial cell barrier function and muted inflammation in resistance to allergic rhinoconjunctivitis from house dust mite challenge JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Ahuja, S. K., Manoharan, M. S., Harper, N. L., Jimenez, F., Hobson, B. D., Martinez, H., Ingale, P., Liu, Y., Carrillo, A., Lou, Z., Kellog, D. L., Ahuja, S. S., Rather, C. G., Esch, R. E., Ramirez, D. A., Clark, R. A., Nadeau, K., Andrews, C. P., Jacobs, R. L., He, W. 2017; 139 (3): 844-854

    Abstract

    An emerging paradigm holds that resistance to the development of allergic diseases, including allergic rhinoconjunctivitis, relates to an intact epithelial/epidermal barrier during early childhood. Conceivably, the immunologic and genomic footprint of this resistance is preserved in nonatopic, nonallergic adults and is unmasked during exposure to an aeroallergen.The aim of this study was to obtain direct support of the epithelial/epidermal barrier model for allergic rhinoconjunctivitis.Twenty-three adults allergic to house dust mites (HDMs) (M+) and 15 nonsensitive, nonallergic (M-) participants completed 3-hour exposures to aerosolized HDM (Dermatophagoides pteronyssinus) powder on 4 consecutive days in an allergen challenge chamber. We analyzed: (1) peripheral blood leukocyte levels and immune responses; and (2) RNA sequencing-derived expression profiles of nasal cells, before and after HDM exposure.On HDM challenge: (1) only M+ persons developed allergic rhinoconjunctivitis symptoms; and (2) peripheral blood leukocyte levels/responses and gene expression patterns in nasal cells were largely concordant between M+ and M- participants; gross differences in these parameters were not observed at baseline (pre-exposure). Two key differences were observed. First, peripheral blood CD4(+) and CD8(+) T-cell activation levels initially decreased in M- participants versus increased in M+ participants. Second, in M- compared with M+ participants, genes that promoted epidermal/epithelial barrier function (eg, filament-aggregating protein [filaggrin]) versus inflammation (eg, chemokines) and innate immunity (interferon) were upregulated versus muted, respectively.An imprint of resistance to HDM challenge in nonatopic, nonallergic adults was muted T-cell activation in the peripheral blood and inflammatory response in the nasal compartment, coupled with upregulation of genes that promote epidermal/epithelial cell barrier function.

    View details for DOI 10.1016/j.jaci.2016.08.019

    View details for Web of Science ID 000397295800017

    View details for PubMedID 27658763

  • Omalizumab facilitates rapid oral desensitization for peanut allergy. journal of allergy and clinical immunology MacGinnitie, A. J., Rachid, R., Gragg, H., Little, S. V., Lakin, P., Cianferoni, A., Heimall, J., Makhija, M., Robison, R., Chinthrajah, R. S., Lee, J., LeBovidge, J., Dominguez, T., Rooney, C., Lewis, M. O., Koss, J., Burke-Roberts, E., Chin, K., Logvinenko, T., Pongracic, J. A., Umetsu, D. T., Spergel, J., Nadeau, K. C., Schneider, L. C. 2017; 139 (3): 873-881 e8

    Abstract

    Peanut oral immunotherapy is a promising approach to peanut allergy, but reactions are frequent, and some patients cannot be desensitized. The anti-IgE medication omalizumab (Xolair; Genentech, South San Francisco, Calif) might allow more rapid peanut updosing and decrease reactions.We sought to evaluate whether omalizumab facilitated rapid peanut desensitization in highly allergic patients.Thirty-seven subjects were randomized to omalizumab (n = 29) or placebo (n = 8). After 12 weeks of treatment, subjects underwent a rapid 1-day desensitization of up to 250 mg of peanut protein, followed by weekly increases up to 2000 mg. Omalizumab was then discontinued, and subjects continued on 2000 mg of peanut protein. Subjects underwent an open challenge to 4000 mg of peanut protein 12 weeks after stopping study drug. If tolerated, subjects continued on 4000 mg of peanut protein daily.The median peanut dose tolerated on the initial desensitization day was 250 mg for omalizumab-treated subjects versus 22.5 mg for placebo-treated subject. Subsequently, 23 (79%) of 29 subjects randomized to omalizumab tolerated 2000 mg of peanut protein 6 weeks after stopping omalizumab versus 1 (12%) of 8 receiving placebo (P < .01). Twenty-three subjects receiving omalizumab versus 1 subject receiving placebo passed the 4000-mg food challenge. Overall reaction rates were not significantly lower in omalizumab-treated versus placebo-treated subjects (odds ratio, 0.57; P = .15), although omalizumab-treated subjects were exposed to much higher peanut doses.Omalizumab allows subjects with peanut allergy to be rapidly desensitized over as little as 8 weeks of peanut oral immunotherapy. In the majority of subjects, this desensitization is sustained after omalizumab is discontinued. Additional studies will help clarify which patients would benefit most from this approach.

    View details for DOI 10.1016/j.jaci.2016.08.010

    View details for PubMedID 27609658

  • Purification and Characterization of a Black Walnut (Juglans nigra) Allergen, Jug n 4 JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY Zhang, Y., Du, W., Fan, Y., Yi, J., Lyu, S., Nadeau, K. C., Thomas, A. L., McHugh, T. 2017; 65 (2): 454-462

    Abstract

    Tree nuts as a group cause a significant number of fatal anaphylactic reactions to foods. Walnuts (Juglans spp.) were one of the leading causes of allergic reactions to tree nuts in the US and Japan. The purpose of this study was to purify and characterize potential food allergens from black walnut. Here, we report the isolation of the black walnuts allergen Jug n 4 (an 11S globulin) by ammonium sulfate precipitation, and hydrophobic interaction and size exclusion chromatography. Reducing SDS-PAGE analysis indicated that purified Jug n 4 consists of 3 major bands. N-terminal sequencing data of these bands indicated that they were the results of a post-transcriptional protease cleavage of the mature protein at a site that consists of a known conserved protease recognition motif, NGXEET. Western blot experiments revealed that 32% of the sera from 25 patients with double-blind, placebo-controlled clinical walnut allergy contained IgE antibodies that recognized Jug n 4, indicating that it is a walnut allergen. Identifying this and additional allergens may facilitate the understanding of the allergenicity of seed storage proteins in tree nuts and their cross-reactivity.

    View details for DOI 10.1021/acs.jafc.6b04387

    View details for Web of Science ID 000392458900024

    View details for PubMedID 27936684

  • Allergen immunotherapy for IgE-mediated food allergy: a systematic review and meta-analysis. Allergy Nurmatov, U., Dhami, S., Arasi, S., Pajno, G. B., Fernandez-Rivas, M., Muraro, A., Roberts, G., Akdis, C., Alvaro-Lozano, M., Beyer, K., Bindslev-Jensen, C., Burks, W., Du Toit, G., Ebisawa, M., Eigenmann, P., Knol, E., Makela, M., Nadeau, K. C., O'mahony, L., Papadopoulos, N., Poulsen, L. K., Sackesen, C., Sampson, H., Santos, A., van Ree, R., Timmermans, F., Sheikh, A. 2017

    Abstract

    The European Academy of Allergy and Clinical Immunology (EAACI) is developing Guidelines for Allergen Immunotherapy (AIT) for IgE-mediated Food Allergy. To inform the development of clinical recommendations, we sought to critically assess evidence on the effectiveness, safety and cost-effectiveness of AIT in the management of food allergy.We undertook a systematic review and meta-analysis that involved searching nine international electronic databases for randomized controlled trials (RCTs) and nonrandomized studies (NRS). Eligible studies were independently assessed by two reviewers against predefined eligibility criteria. The quality of studies was assessed using the Cochrane Risk of Bias tool for RCTs and the Cochrane ACROBAT-NRS tool for quasi-RCTs. Random-effects meta-analyses were undertaken, with planned subgroup and sensitivity analyses.We identified 1814 potentially relevant papers from which we selected 31 eligible studies, comprising of 25 RCTs and six NRS, studying a total of 1259 patients. Twenty-five trials evaluated oral immunotherapy (OIT), five studies investigated sublingual immunotherapy, and one study evaluated epicutaneous immunotherapy. The majority of these studies were in children. Twenty-seven studies assessed desensitization, and nine studies investigated sustained unresponsiveness postdiscontinuation of AIT. Meta-analyses demonstrated a substantial benefit in terms of desensitization (risk ratio (RR) = 0.16, 95% CI 0.10, 0.26) and suggested, but did not confirm sustained unresponsiveness (RR = 0.29, 95% CI 0.08, 1.13). Only one study reported on disease-specific quality of life (QoL), which reported no comparative results between OIT and control group. Meta-analyses revealed that the risk of experiencing a systemic adverse reaction was higher in those receiving AIT, with a more marked increase in the risk of local adverse reactions. Sensitivity analysis excluding those studies judged to be at high risk of bias demonstrated the robustness of summary estimates of effectiveness and safety of AIT for food allergy. None of the studies reported data on health economic analyses.AIT may be effective in raising the threshold of reactivity to a range of foods in children with IgE-mediated food allergy whilst receiving (i.e. desensitization) and post-discontinuation of AIT. It is, however, associated with a modest increased risk in serious systemic adverse reactions and a substantial increase in minor local adverse reactions. More data are needed in relation to adults, long term effects, the impact on QoL and the cost-effectiveness of AIT.

    View details for DOI 10.1111/all.13124

    View details for PubMedID 28058751

  • Modified High-Molecular-Weight Hyaluronan Promotes Allergen-Specific Immune Tolerance AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY Gebe, J. A., Yadava, K., Ruppert, S. M., Marshall, P., Hill, P., Falk, B. A., Sweere, J. M., Han, H., Kaber, G., Medina, C., Mikecz, K., Ziegler, S. F., Balaji, S., Keswani, S. G., Perez, V. A., Butte, M. J., Nadeau, K., Altemeier, W. A., Fanger, N., Bollyky, P. L. 2017; 56 (1): 109-120
  • Effectiveness of air purifier on health outcomes and indoor particles in homes of children with allergic diseases in Fresno, California: A pilot study JOURNAL OF ASTHMA Park, H., Cheng, K., Tetteh, A. O., Hildemann, L. M., Nadeau, K. C. 2017; 54 (4): 341-346
  • Deciphering the black box of food allergy mechanisms. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology Sampath, V., Tupa, D., Graham, M. T., Chatila, T. A., Spergel, J. M., Nadeau, K. C. 2017; 118 (1): 21-27

    Abstract

    To review our current understanding of immunotherapy, the immune mechanisms underlying food allergy, and the methodological advances that are furthering our understanding of the role of immune cells and other molecules in mediating food allergies.Literature searches were performed using the following combination of terms: allergy, immunotherapy, food, and mechanisms. Data from randomized clinical studies using state-of-the-art mechanistic tools were prioritized.Articles were selected based on their relevance to food allergy.Current standard of care for food allergies is avoidance of allergenic foods and the use of epinephrine in case of severe reaction during unintentional ingestion. During the last few decades, great strides have been made in understanding the cellular and molecular mechanisms underlying food allergy, and this information is spearheading the development of exciting new treatments.Immunotherapy protocols are effective in desensitizing individuals to specific allergens; however, recurrence of allergic sensitization is common after discontinuation of therapy. Interestingly, in a subset of individuals, immunotherapy is protective against allergens even after discontinuation of immunotherapy. Whether this protection is permanent is currently unknown because of inadequate long-term follow-up data. Research on understanding the underlying mechanisms may assist in modifying protocols to improve outcome and enable sustained unresponsiveness, rather than a temporary relief against food allergies. The cellular changes brought about by immunotherapy are still a black box, but major strides in our understanding are being made at an exciting pace.

    View details for DOI 10.1016/j.anai.2016.10.017

    View details for PubMedID 28007085

  • Food allergy: immune mechanisms, diagnosis and immunotherapy NATURE REVIEWS IMMUNOLOGY Yu, W., Freeland, D. M., Nadeau, K. C. 2016; 16 (12): 751-765

    Abstract

    Food allergy is a pathological, potentially deadly, immune reaction triggered by normally innocuous food protein antigens. The prevalence of food allergies is rising and the standard of care is not optimal, consisting of food-allergen avoidance and treatment of allergen-induced systemic reactions with adrenaline. Thus, accurate diagnosis, prevention and treatment are pressing needs, research into which has been catalysed by technological advances that are enabling a mechanistic understanding of food allergy at the cellular and molecular levels. We discuss the diagnosis and treatment of IgE-mediated food allergy in the context of the immune mechanisms associated with healthy tolerance to common foods, the inflammatory response underlying most food allergies, and immunotherapy-induced desensitization. We highlight promising research advances, therapeutic innovations and the challenges that remain.

    View details for DOI 10.1038/nri.2016.111

    View details for Web of Science ID 000389134500010

    View details for PubMedID 27795547

  • Identification, characterization, and initial epitope mapping of pine nut allergen Pin k 2 FOOD RESEARCH INTERNATIONAL Zhang, Y., Du, W., Fan, Y., Yi, J., Lyu, S., Nadeau, K. C., McHugh, T. H. 2016; 90: 268-274
  • Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency. journal of clinical investigation Walter, J. E., Rosen, L. B., Csomos, K., Rosenberg, J. M., Mathew, D., Keszei, M., Ujhazi, B., Chen, K., Lee, Y. N., Tirosh, I., Dobbs, K., Al-Herz, W., Cowan, M. J., Puck, J., Bleesing, J. J., Grimley, M. S., Malech, H., De Ravin, S. S., Gennery, A. R., Abraham, R. S., Joshi, A. Y., Boyce, T. G., Butte, M. J., Nadeau, K. C., Balboni, I., Sullivan, K. E., Akhter, J., Adeli, M., El-Feky, R. A., El-Ghoneimy, D. H., Dbaibo, G., Wakim, R., Azzari, C., Palma, P., Cancrini, C., Capuder, K., Condino-Neto, A., Costa-Carvalho, B. T., Oliveira, J. B., Roifman, C., Buchbinder, D., Kumanovics, A., Franco, J. L., Niehues, T., Schuetz, C., Kuijpers, T., Yee, C., Chou, J., Masaad, M. J., Geha, R., Uzel, G., Gelman, R., Holland, S. M., Recher, M., Utz, P. J., Browne, S. K., Notarangelo, L. D. 2016; 126 (11): 4389-?

    View details for DOI 10.1172/JCI91162

    View details for PubMedID 27801680

    View details for PubMedCentralID PMC5096894

  • Epigenetic Changes During Food-Specific Immunotherapy. Current allergy and asthma reports Bunning, B. J., DeKruyff, R. H., Nadeau, K. C. 2016; 16 (12): 87-?

    Abstract

    The prevalence and severity of IgE-mediated food allergy has increased dramatically over the last 15 years and is becoming a global health problem. Multiple lines of evidence suggest that epigenetic modifications of the genome resulting from gene-environment interactions have a key role in the increased prevalence of atopic disease. In this review, we describe the recent evidence suggesting how epigenetic changes mediate susceptibility to food allergies, and discuss how immunotherapy (IT) may reverse these effects. We discuss the areas of the epigenome as yet unexplored in terms of food allergy and IT such as histone modification and chromatin accessibility, and new techniques that may be utilized in future studies.Recent findings provide strong evidence that DNA methylation of certain promoter regions such as Forkhead box protein 3 is associated with clinical reactivity, and further, can be changed during IT treatment. Reports on other epigenetic changes are limited but also show evidence of significant change based on both disease status and treatment. In comparison to epigenetic studies focusing on asthma and allergic rhinitis, food allergy remains understudied. However, within the next decade, it is likely that epigenetic modifications may be used as biomarkers to aid in diagnosis and treatment of food-allergic patients. DNA methylation at specific loci has shown associations between food challenge outcomes, successful desensitization treatment, and overall phenotype compared to healthy controls.

    View details for PubMedID 27943047

  • Effectiveness of air purifier on health outcomes and indoor particles in homes of children with allergic diseases in Fresno, California: A pilot study. journal of asthma Park, H., Cheng, K., Tetteh, A. O., Hildemann, L. M., Nadeau, K. C. 2016: 1-6

    Abstract

    Epidemiologic studies indicate that indoor air pollution is correlated with morbidity caused by allergic diseases. We evaluated the effectiveness of reducing the levels of indoor fine particulate matter <2.5 micrometer diameter (PM2.5) in Fresno, California using air purifiers on health outcomes in children with asthma and/or allergic rhinitis.The active group (with air purifiers) and the control group consisted of eight houses each. Air purifiers were installed in the living rooms and bedrooms of the subjects in the active group during the entire 12-week study duration. Childhood asthma control test, peak flow rate monitoring, and nasal symptom scores were evaluated at weeks 0, 6, and 12.At 12 weeks, the active group showed a trend toward an improvement of childhood asthma control test scores and mean evening peak flow rates, whereas the control group showed deterioration in the same measures. Total and daytime nasal symptoms scores significantly reduced in the active group (p = 0.001 and p = 0.011, respectively). The average indoor PM2.5 concentrations reduced by 43% (7.42 to 4.28 μg/m(3)) in the active group (p = 0.001).Intervention with air purifiers reduces indoor PM2.5 levels with significant improvements in nasal symptoms in children with allergic rhinitis in Fresno.

    View details for PubMedID 27723364

  • Advances in food allergy oral immunotherapy: toward tolerance. Current opinion in immunology Hussey Freeland, D. M., Fan-Minogue, H., Spergel, J. M., Chatila, T. A., Nadeau, K. C. 2016; 42: 119-123

    Abstract

    The incidence of food allergy, a disease characterized by adverse immune responses that can render common foods life-threatening, is rising. Yet our current standard of care is simply avoidance of allergenic foods and administration of emergency medications upon accidental exposure. Significant advances have been made in food allergy oral immunotherapy, which is emerging as a potential preventive and curative treatment for this disease. The fundamental strategy of oral immunotherapy is to mitigate adverse immune responses to allergenic food proteins through repeated exposure; reduced reactivity to food allergens (desensitization) often results, but the establishment of sustained immune unresponsiveness or of permanent resolution (tolerance) is not certain. This review examines exciting recent developments in oral immunotherapy for food allergy.

    View details for DOI 10.1016/j.coi.2016.08.002

    View details for PubMedID 27745972

  • Advances in food allergy oral immunotherapy: toward tolerance CURRENT OPINION IN IMMUNOLOGY Freeland, D. M., Fan-Minogue, H., Spergel, J. M., Chatila, T. A., Nadeau, K. C. 2016; 42: 119-123
  • Temporal Regulation by Innate Type 2 Cytokines in Food Allergies. Current allergy and asthma reports Graham, M. T., Andorf, S., Spergel, J. M., Chatila, T. A., Nadeau, K. C. 2016; 16 (10): 75-?

    Abstract

    Food allergies (FAs) are a growing epidemic in western countries with poorly defined etiology. Defined as an adverse immune response to common food allergens, FAs present heterogeneously as a single- or multi-organ response that ranges in severity from localized hives and angioedema to systemic anaphylaxis.Current research focusing on epithelial-derived cytokines contends that temporal regulation by these factors impact initial sensitization and persistence of FA responses upon repeated food allergen exposure. Mechanistic understanding of FA draws insight from a myriad of atopic conditions studied in humans and modeled in mice. In this review, we will highlight how epithelial-derived cytokines initiate and then potentiate FAs. We will also review existing evidence of the contribution of other atopic diseases to FA pathogenesis and whether FA symptoms overlap with other atopic diseases.

    View details for PubMedID 27771884

  • Modified High Molecular Weight Hyaluronan Promotes Allergen-Specific Immune Tolerance. American journal of respiratory cell and molecular biology Gebe, J. A., Yadava, K., Ruppert, S. M., Marshall, P., Hill, P., Falk, B. A., Sweere, J. M., Han, H., Kaber, G., Medina, C., Mikecz, K., Ziegler, S. F., Balaji, S., Keswani, S. G., de Jesus Perez, V. A., Butte, M. J., Nadeau, K., Altemeier, W. A., Fanger, N., Bollyky, P. L. 2016: -?

    Abstract

    The extracellular matrix in asthmatic lungs contains abundant low-molecular-weight hyaluronan, and this is known to promote antigen presentation and allergic responses. Conversely, high-molecular-weight hyaluronan (HMW-HA), typical of uninflamed tissues, is known to suppress inflammation. We investigated whether HMW-HA can be adapted to promote tolerance to airway allergens. HMW-HA was thiolated to prevent its catabolism and was tethered to allergens via thiol linkages. This platform, which we call "XHA," delivers antigenic payloads in the context of antiinflammatory costimulation. Allergen/XHA was administered intranasally to mice that had been sensitized previously to these allergens. XHA prevents allergic airway inflammation in mice sensitized previously to either ovalbumin or cockroach proteins. Allergen/XHA treatment reduced inflammatory cell counts, airway hyperresponsiveness, allergen-specific IgE, and T helper type 2 cell cytokine production in comparison with allergen alone. These effects were allergen specific and IL-10 dependent. They were durable for weeks after the last challenge, providing a substantial advantage over the current desensitization protocols. Mechanistically, XHA promoted CD44-dependent inhibition of nuclear factor-κB signaling, diminished dendritic cell maturation, and reduced the induction of allergen-specific CD4 T-helper responses. XHA and other potential strategies that target CD44 are promising alternatives for the treatment of asthma and allergic sinusitis.

    View details for PubMedID 27598620

    View details for PubMedCentralID PMC5248962

  • Assessing basophil activation by using flow cytometry and mass cytometry in blood stored 24 hours before analysis. journal of allergy and clinical immunology Mukai, K., Gaudenzio, N., Gupta, S., Vivanco, N., Bendall, S. C., Maecker, H. T., Chinthrajah, R. S., Tsai, M., Nadeau, K. C., Galli, S. J. 2016

    Abstract

    Basophil activation tests (BATs) have promise for research and for clinical monitoring of patients with allergies. However, BAT protocols vary in blood anticoagulant used and temperature and time of storage before testing, complicating comparisons of results from various studies.We attempted to establish a BAT protocol that would permit analysis of blood within 24 hours of obtaining the sample.Blood from 46 healthy donors and 120 patients with peanut allergy was collected into EDTA or heparin tubes, and samples were stored at 4°C or room temperature for 4 or 24 hours before performing BATs.Stimulation with anti-IgE or IL-3 resulted in strong upregulation of basophil CD203c in samples collected in EDTA or heparin, stored at 4°C, and analyzed 24 hours after sample collection. However, a CD63(hi) population of basophils was not observed in any conditions in EDTA-treated samples unless exogenous calcium/magnesium was added at the time of anti-IgE stimulation. By contrast, blood samples collected in heparin tubes were adequate for quantification of upregulation of basophil CD203c and identification of a population of CD63(hi) basophils, irrespective of whether the specimens were analyzed by means of conventional flow cytometry or cytometry by time-of-flight mass spectrometry, and such tests could be performed after blood was stored for 24 hours at 4°C.BATs to measure upregulation of basophil CD203c and induction of a CD63(hi) basophil population can be conducted with blood obtained in heparin tubes and stored at 4°C for 24 hours.

    View details for DOI 10.1016/j.jaci.2016.04.060

    View details for PubMedID 27527263

    View details for PubMedCentralID PMC5237629

  • Giant magnetoresistive sensor array for sensitive and specific multiplexed food allergen detection BIOSENSORS & BIOELECTRONICS Ng, E., Nadeau, K. C., Wang, S. X. 2016; 80: 359-365
  • Infant Infections and Respiratory Symptoms in Relation to in Utero Arsenic Exposure in a US Cohort ENVIRONMENTAL HEALTH PERSPECTIVES Farzan, S. F., Li, Z., Korrick, S. A., Spiegelman, D., Enelow, R., Nadeau, K., Baker, E., Karagas, M. R. 2016; 124 (6): 840-847

    Abstract

    Arsenic has been linked to disrupted immune function and greater infection susceptibility in highly exposed populations. Well arsenic levels above the U.S. EPA limit occur in our U.S. study area and are of particular concern for pregnant women and infants.We investigated whether in utero arsenic exposure affects the risk of infections and respiratory symptoms over the first year of life.We prospectively obtained information on infant infections and symptoms, including their duration and treatment (n = 412) at 4, 8, and 12 months using a parental telephone survey. Using generalized estimating equation models adjusted for potential confounders, we evaluated the association between maternal pregnancy urinary arsenic and infant infections and symptoms over the first year.Each doubling of maternal urinary arsenic was related to increases in the total number of infections requiring prescription medication in the first year [relative risk (RR) = 1.1; 95% CI: 1.0, 1.2]. Urinary arsenic was related specifically to respiratory symptoms (difficulty breathing, wheezing, and cough) lasting ≥ 2 days or requiring prescription medication (RR = 1.1; 95% CI: 1.0, 1.2; and RR = 1.2; 95% CI: 1.0, 1.5, respectively), and wheezing lasting ≥ 2 days, resulting in a doctor visit or prescription medication treatment (RR = 1.3; 95% CI: 1.0, 1.7; RR = 1.3; 95% CI: 1.0, 1.8, and RR = 1.5; 95% CI: 1.0, 2.2, respectively). Associations also were observed with diarrhea (RR = 1.4; 95% CI: 1.1, 1.9) and fever resulting in a doctor visit (RR = 1.2; 95% CI: 1.0, 1.5).In utero arsenic exposure was associated with a higher risk of infection during the first year of life in our study population, particularly infections requiring medical treatment, and with diarrhea and respiratory symptoms.Farzan SF, Li Z, Korrick SA, Spiegelman D, Enelow R, Nadeau K, Baker E, Karagas MR. 2016. Infant infections and respiratory symptoms in relation to in utero arsenic exposure in a U.S.Environ Health Perspect 124:840-847; http://dx.doi.org/10.1289/ehp.1409282.

    View details for DOI 10.1289/ehp.1409282

    View details for Web of Science ID 000377081300028

    View details for PubMedID 26359651

  • Identification and Characterization of a New Pecan [Carya illinoinensis (Wangenh.) K. Koch] Allergen, Car i 2 JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY Zhang, Y., Lee, B., Du, W., Lyu, S., Nadeau, K. C., Grauke, L. J., Zhang, Y., Wang, S., Fan, Y., Yi, J., McHugh, T. H. 2016; 64 (20): 4146-4151

    Abstract

    The 7S vicilin and 11S legumin seed storage globulins belong to the cupin protein superfamily and are major food allergens in many foods from the "big eight" food allergen groups. Here, for the first time, pecan vicilin was found to be a food allergen. Western blot experiments revealed that 30% of 27 sera used in this study and 24% of the sera from 25 patients with double-blind, placebo controlled clinical pecan allergy contained IgE antibodies specific to pecan vicilin. This allergen consists of a low-complexity region at its N-terminal and a structured domain at the C-terminal that contains two cupin motifs and forms homotrimers. The crystal structure of recombinant pecan vicilin was determined. The refined structure gave R/Rfree values of 0.218/0.262 for all data to 2.65 Å. There were two trimeric biological units in the crystallographic asymmetric unit. Pecan vicilin is also a copper protein. These data may facilitate the understanding of the nutritional value and the allergenicity relevance of the copper binding property of seed storage proteins in tree nuts.

    View details for DOI 10.1021/acs.jafc.6b00884

    View details for Web of Science ID 000376825600025

    View details for PubMedID 27128197

  • Structural basis of omalizumab therapy and omalizumab-mediated IgE exchange NATURE COMMUNICATIONS Pennington, L. F., Tarchevskaya, S., Brigger, D., Sathiyamoorthy, K., Graham, M. T., Nadeau, K. C., Eggel, A., Jardetzky, T. S. 2016; 7

    Abstract

    Omalizumab is a widely used therapeutic anti-IgE antibody. Here we report the crystal structure of the omalizumab-Fab in complex with an IgE-Fc fragment. This structure reveals the mechanism of omalizumab-mediated inhibition of IgE interactions with both high- and low-affinity IgE receptors, and explains why omalizumab selectively binds free IgE. The structure of the complex also provides mechanistic insight into a class of disruptive IgE inhibitors that accelerate the dissociation of the high-affinity IgE receptor from IgE. We use this structural data to generate a mutant IgE-Fc fragment that is resistant to omalizumab binding. Treatment with this omalizumab-resistant IgE-Fc fragment, in combination with omalizumab, promotes the exchange of cell-bound full-length IgE with omalizumab-resistant IgE-Fc fragments on human basophils. This combination treatment also blocks basophil activation more efficiently than either agent alone, providing a novel approach to probe regulatory mechanisms underlying IgE hypersensitivity with implications for therapeutic interventions.

    View details for DOI 10.1038/ncomms11610

    View details for Web of Science ID 000376111500001

    View details for PubMedID 27194387

    View details for PubMedCentralID PMC4873975

  • Molecular and cellular mechanisms of food allergy and food tolerance. journal of allergy and clinical immunology Chinthrajah, R. S., Hernandez, J. D., Boyd, S. D., Galli, S. J., Nadeau, K. C. 2016; 137 (4): 984-997

    Abstract

    Ingestion of innocuous antigens, including food proteins, normally results in local and systemic immune nonresponsiveness in a process termed oral tolerance. Oral tolerance to food proteins is likely to be intimately linked to mechanisms that are responsible for gastrointestinal tolerance to large numbers of commensal microbes. Here we review our current understanding of the immune mechanisms responsible for oral tolerance and how perturbations in these mechanisms might promote the loss of oral tolerance and development of food allergies. Roles for the commensal microbiome in promoting oral tolerance and the association of intestinal dysbiosis with food allergy are discussed. Growing evidence supports cutaneous sensitization to food antigens as one possible mechanism leading to the failure to develop or loss of oral tolerance. A goal of immunotherapy for food allergies is to induce sustained desensitization or even true long-term oral tolerance to food allergens through mechanisms that might in part overlap with those associated with the development of natural oral tolerance.

    View details for DOI 10.1016/j.jaci.2016.02.004

    View details for PubMedID 27059726

  • A randomized, double-blind, placebo-controlled study of omalizumab combined with oral immunotherapy for the treatment of cow's milk allergy JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Wood, R. A., Kim, J. S., Lindblad, R., Nadeau, K., Henning, A. K., Dawson, P., Plaut, M., Sampson, H. A. 2016; 137 (4): 1103-?

    Abstract

    Although studies of oral immunotherapy (OIT) for food allergy have shown promise, treatment is frequently complicated by adverse reactions and, even when successful, has limited long-term efficacy because benefits usually diminish when treatment is discontinued.We sought to examine whether the addition of omalizumab to milk OIT reduces treatment-related reactions, improves outcomes, or both.This was a double-blind, placebo-controlled trial with subjects randomized to omalizumab or placebo. Open-label milk OIT was initiated after 4 months of omalizumab/placebo with escalation to maintenance over 22 to 40 weeks, followed by daily maintenance dosing through month 28. At month 28, omalizumab was discontinued, and subjects passing an oral food challenge (OFC) continued OIT for 8 weeks, after which OIT was discontinued with rechallenge at month 32 to assess sustained unresponsiveness (SU).Fifty-seven subjects (7-32 years) were randomized, with no significant baseline differences in age, milk-specific IgE levels, skin test results, or OFC results. At month 28, 24 (88.9%) omalizumab-treated subjects and 20 (71.4%) placebo-treated subjects passed the 10-g "desensitization" OFC (P = .18). At month 32, SU was demonstrated in 48.1% in the omalizumab group and 35.7% in the placebo group (P = .42). Adverse reactions were markedly reduced during OIT escalation in omalizumab-treated subjects for percentages of doses per subject provoking symptoms (2.1% vs 16.1%, P = .0005), dose-related reactions requiring treatment (0.0% vs 3.8%, P = .0008), and doses required to achieve maintenance (198 vs 225, P = .008).In this first randomized, double-blind, placebo-controlled trial of omalizumab in combination with food OIT, we found significant improvements in measurements of safety but not in outcomes of efficacy (desensitization and SU).

    View details for DOI 10.1016/j.jaci.2015.10.005

    View details for Web of Science ID 000373351200016

    View details for PubMedID 26581915

  • Personal exposure to airborne particulate matter due to residential dryer lint cleaning BUILDING AND ENVIRONMENT Cheng, K., Zheng, D., Tetteh, A. O., Park, H., Nadeau, K. C., Hildemann, L. M. 2016; 98: 145-149
  • T-Cell Immunophenotyping of Second-Hand Smoke-related Asthma. Annals of the American Thoracic Society Bauer, R. N., Chinthrajah, R. S., Andorf, S., Hobson, B., Miller, R. L., Nadeau, K. C. 2016; 13: S95-?

    View details for DOI 10.1513/AnnalsATS.201507-457MG

    View details for PubMedID 27027962

  • Successful immunotherapy induces previously unidentified allergen-specific CD4+ T-cell subsets. Proceedings of the National Academy of Sciences of the United States of America Ryan, J. F., Hovde, R., Glanville, J., Lyu, S., Ji, X., Gupta, S., Tibshirani, R. J., Jay, D. C., Boyd, S. D., Chinthrajah, R. S., Davis, M. M., Galli, S. J., Maecker, H. T., Nadeau, K. C. 2016; 113 (9): E1286-95

    Abstract

    Allergen immunotherapy can desensitize even subjects with potentially lethal allergies, but the changes induced in T cells that underpin successful immunotherapy remain poorly understood. In a cohort of peanut-allergic participants, we used allergen-specific T-cell sorting and single-cell gene expression to trace the transcriptional "roadmap" of individual CD4+ T cells throughout immunotherapy. We found that successful immunotherapy induces allergen-specific CD4+ T cells to expand and shift toward an "anergic" Th2 T-cell phenotype largely absent in both pretreatment participants and healthy controls. These findings show that sustained success, even after immunotherapy is withdrawn, is associated with the induction, expansion, and maintenance of immunotherapy-specific memory and naive T-cell phenotypes as early as 3 mo into immunotherapy. These results suggest an approach for immune monitoring participants undergoing immunotherapy to predict the success of future treatment and could have implications for immunotherapy targets in other diseases like cancer, autoimmune disease, and transplantation.

    View details for DOI 10.1073/pnas.1520180113

    View details for PubMedID 26811452

    View details for PubMedCentralID PMC4780622

  • Single B-cell deconvolution of peanut-specific antibody responses in allergic patients JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Hoh, R. A., Joshi, S. A., Liu, Y., Wang, C., Roskin, K. M., Lee, J., Pham, T., Looney, T. J., Jackson, K. J., Dixit, V. P., King, J., Lyu, S., Jenks, J., Hamilton, R. G., Nadeau, K. C., Boyd, S. D. 2016; 137 (1): 157-167

    Abstract

    The frequencies, cellular phenotypes, epitope specificity, and clonal diversity of allergen-specific B cells in patients with food allergy are not fully understood but are of major pathogenic and therapeutic significance.We sought to characterize peanut allergen-specific B-cell populations and the sequences and binding activities of their antibodies before and during immunotherapy.B cells binding fluorescently labeled Ara h 1 or Ara h 2 were phenotyped and isolated by means of flow cytometric sorting from 18 patients at baseline and 13 patients during therapy. Fifty-seven mAbs derived from allergen-binding single B cells were evaluated by using ELISA, Western blotting, and peptide epitope mapping. Deep sequencing of the B-cell repertoires identified additional members of the allergen-specific B-cell clones.Median allergen-binding B-cell frequencies were 0.0097% (Ara h 1) or 0.029% (Ara h 2) of B cells in baseline blood from allergic patients and approximately 3-fold higher during immunotherapy. Five of 57 allergen-specific cells belonged to clones containing IgE-expressing members. Almost all allergen-specific antibodies were mutated, and binding to both conformational and linear allergen epitopes was detected. Increasing somatic mutation of IgG4 members of a clone was seen in immunotherapy, whereas IgE mutation levels in the clone did not increase.Most peanut allergen-binding B cells isolated by means of antigen-specific flow sorting express mutated and isotype-switched antibodies. Immunotherapy increases their frequency in the blood, and even narrowly defined allergen epitopes are recognized by numerous distinct B-cell clones in a patient. The results also suggest that oral immunotherapy can stimulate somatic mutation of allergen-specific IgG4.

    View details for DOI 10.1016/j.jaci.2015.05.029

    View details for Web of Science ID 000367724300006

  • Allergen immunotherapy for IgE-mediated food allergy: protocol for a systematic review. Clinical and translational allergy Dhami, S., Nurmatov, U., Pajno, G. B., Fernandez-Rivas, M., Muraro, A., Roberts, G., Akdis, C., Alvaro-Lozano, M., Beyer, K., Bindslev-Jensen, C., Burks, W., Du Toit, G., Ebisawa, M., Eigenmann, P., Knol, E., Makela, M., Nadeau, K. C., O'mahony, L., Papadopoulos, N., Poulsen, L., Sackesen, C., Sampson, H., Santos, A., van Ree, R., Timmermans, F., Sheikh, A. 2016; 6: 24-?

    Abstract

    The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing the EAACI Guidelines for Allergen Immunotherapy (AIT) for IgE-mediated food allergy. We seek to critically assess the effectiveness, cost-effectiveness and safety of AIT in IgE-mediated food allergy.We will undertake a systematic review, which will involve searching international biomedical databases for published, in progress and unpublished evidence. Studies will be independently screened against pre-defined eligibility criteria and critically appraised using established instruments. Data will be descriptively and, if possible and appropriate, quantitatively synthesised.The findings from this review will be used to inform the development of recommendations for EAACI's Guidelines on AIT.

    View details for DOI 10.1186/s13601-016-0113-z

    View details for PubMedID 27382460

  • Pilot randomised trial of a healthy eating behavioural intervention in uncontrolled asthma EUROPEAN RESPIRATORY JOURNAL Ma, J., Strub, P., Lv, N., Xiao, L., Camargo, C. A., Buist, A. S., Lavori, P. W., Wilson, S. R., Nadeau, K. C., Rosas, L. G. 2016; 47 (1): 122-132
  • Mixing and sink effects of air purifiers on indoor PM2.5 concentrations: A pilot study of eight residential homes in Fresno, California AEROSOL SCIENCE AND TECHNOLOGY Cheng, K., Park, H., Tetteh, A. O., Zheng, D., Ouellette, N. T., Nadeau, K. C., Hildemann, L. M. 2016; 50 (8): 835-845
  • Diagnosis of Food Allergy PEDIATRIC CLINICS OF NORTH AMERICA Chinthrajah, R. S., Tupa, D., Prince, B. T., Block, W. M., Rosa, J. S., Singh, A. M., Nadeau, K. 2015; 62 (6): 1393-?

    View details for DOI 10.1016/j.pcl.2015.07.009

    View details for Web of Science ID 000364106500005

    View details for PubMedID 26456439

  • Future Research Directions in Asthma An NHLBI Working Group Report AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Levy, B. D., Noel, P. J., Freemer, M. M., Cloutier, M. M., Georas, S. N., Jarjour, N. N., Ober, C., Woodruff, P., Barnes, K. C., Bender, B. G., Camargo, C. A., Chupp, G. L., Denlinger, L. C., Fahy, J. V., Fitzpatrick, A. M., Fuhlbrigge, A., Gaston, B. M., Hartert, T. V., Kolls, J. K., Lynch, S. V., Moore, W. C., Morgan, W. J., Nadeau, K. C., Ownby, D. R., Solway, J., Szefler, S. J., Wenzel, S. E., Wright, R. J., Smith, R. A., Erzurum, S. C. 2015; 192 (11): 1366-1372

    View details for DOI 10.1164/rccm.201505-0963WS

    View details for Web of Science ID 000365829900017

    View details for PubMedID 26305520

  • Gut Microbiome and the Development of Food Allergy and Allergic Disease PEDIATRIC CLINICS OF NORTH AMERICA Prince, B. T., Mandel, M. J., Nadeau, K., Singh, A. M. 2015; 62 (6): 1479-?

    View details for DOI 10.1016/j.pcl.2015.07.007

    View details for Web of Science ID 000364106500011

    View details for PubMedID 26456445

  • Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency JOURNAL OF CLINICAL INVESTIGATION Walter, J. E., Rosen, L. B., Csomos, K., Rosenberg, J. M., Mathew, D., Keszei, M., Ujhazi, B., Chen, K., Lee, Y. N., Tirosh, I., Dobbs, K., Al-Herz, W., Cowan, M. J., Puck, J., Bleesing, J. J., Grimley, M. S., Malech, H., De Ravin, S. S., Gennery, A. R., Abraham, R. S., Joshi, A. Y., Boyce, T. G., Butte, M. J., Nadeau, K. C., Balboni, I., Sullivan, K. E., Akhter, J., Adeli, M., El-Feky, R. A., El-Ghoneimy, D. H., Dbaibo, G., Wakim, R., Azzari, C., Palma, P., Cancrini, C., Capuder, K., Condino-Neto, A., Costa-Carvalho, B. T., Oliveira, J. B., Roifman, C., Buchbinder, D., Kumanovics, A., Luis Franco, J., Niehues, T., Schuetz, C., Kuijpers, T., Yee, C., Chou, J., Masaad, M. J., Geha, R., Uze, G., Gelman, R., Holland, S. M., Recher, M., Utz, P. J., Browne, S. K., Notarangelo, L. D. 2015; 125 (11): 4135-4148

    Abstract

    Patients with mutations of the recombination-activating genes (RAG) present with diverse clinical phenotypes, including severe combined immune deficiency (SCID), autoimmunity, and inflammation. However, the incidence and extent of immune dysregulation in RAG-dependent immunodeficiency have not been studied in detail. Here, we have demonstrated that patients with hypomorphic RAG mutations, especially those with delayed-onset combined immune deficiency and granulomatous/autoimmune manifestations (CID-G/AI), produce a broad spectrum of autoantibodies. Neutralizing anti-IFN-α or anti-IFN-ω antibodies were present at detectable levels in patients with CID-G/AI who had a history of severe viral infections. As this autoantibody profile is not observed in a wide range of other primary immunodeficiencies, we hypothesized that recurrent or chronic viral infections may precipitate or aggravate immune dysregulation in RAG-deficient hosts. We repeatedly challenged Rag1S723C/S723C mice, which serve as a model of leaky SCID, with agonists of the virus-recognizing receptors TLR3/MDA5, TLR7/-8, and TLR9 and found that this treatment elicits autoantibody production. Altogether, our data demonstrate that immune dysregulation is an integral aspect of RAG-associated immunodeficiency and indicate that environmental triggers may modulate the phenotypic expression of autoimmune manifestations.

    View details for DOI 10.1172/JCI80477

    View details for Web of Science ID 000364110000017

    View details for PubMedID 26457731

  • Human in vitro induced T regulatory cells and memory T cells share common demethylation of specific FOXP3 promoter region CLINICAL AND TRANSLATIONAL ALLERGY Begin, P., Schulze, J., Baron, U., Olek, S., Bauer, R. N., Passerini, L., Baccheta, R., Nadeau, K. C. 2015; 5
  • IgH sequences in common variable immune deficiency reveal altered B cell development and selection. Science translational medicine Roskin, K. M., Simchoni, N., Liu, Y., Lee, J., Seo, K., Hoh, R. A., Pham, T., Park, J. H., Furman, D., Dekker, C. L., Davis, M. M., James, J. A., Nadeau, K. C., Cunningham-Rundles, C., Boyd, S. D. 2015; 7 (302): 302ra135-?

    Abstract

    Common variable immune deficiency (CVID) is the most common symptomatic primary immune deficiency, affecting ~1 in 25,000 persons. These patients suffer from impaired antibody responses, autoimmunity, and susceptibility to lymphoid cancers. To explore the cellular basis for these clinical phenotypes, we conducted high-throughput DNA sequencing of immunoglobulin heavy chain gene rearrangements from 93 CVID patients and 105 control subjects and sorted naïve and memory B cells from 13 of the CVID patients and 10 of the control subjects. The CVID patients showed abnormal VDJ rearrangement and abnormal formation of complementarity-determining region 3 (CDR3). We observed a decreased selection against antibodies with long CDR3s in memory repertoires and decreased variable gene replacement, offering possible mechanisms for increased patient autoreactivity. Our data indicate that patient immunodeficiency might derive from both decreased diversity of the naïve B cell pool and decreased somatic hypermutation in memory repertoires. The CVID patients also exhibited an abnormal clonal expansion of unmutated B cells relative to the controls. Although impaired B cell germinal center activation is commonly viewed as causative in CVID, these data indicate that CVID B cells diverge from controls as early as the pro-B stage, cell and suggest possible explanations for the increased incidence of autoimmunity, immunodeficiency, and lymphoma CVID patients.

    View details for DOI 10.1126/scitranslmed.aab1216

    View details for PubMedID 26311730

  • IgH sequences in common variable immune deficiency reveal altered B cell development and selection. Science translational medicine Roskin, K. M., Simchoni, N., Liu, Y., Lee, J., Seo, K., Hoh, R. A., Pham, T., Park, J. H., Furman, D., Dekker, C. L., Davis, M. M., James, J. A., Nadeau, K. C., Cunningham-Rundles, C., Boyd, S. D. 2015; 7 (302): 302ra135-?

    View details for DOI 10.1126/scitranslmed.aab1216

    View details for PubMedID 26311730

  • The role of epigenetic mediation and the future of food allergy research SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY Quake, C., Nadeau, K. C. 2015; 43: 125-130

    View details for DOI 10.1016/j.semcdb.2015.07.002

    View details for Web of Science ID 000364887100015

    View details for PubMedID 26150170

  • PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity. journal of allergy and clinical immunology Mathieu, A., Verronese, E., Rice, G. I., Fouyssac, F., Bertrand, Y., Picard, C., Chansel, M., Walter, J. E., Notarangelo, L. D., Butte, M. J., Nadeau, K. C., Csomos, K., Chen, D. J., Chen, K., Delgado, A., Rigal, C., Bardin, C., Schuetz, C., Moshous, D., Reumaux, H., Plenat, F., Phan, A., Zabot, M., Balme, B., Viel, S., Bienvenu, J., Cochat, P., van der Burg, M., Caux, C., Kemp, E. H., Rouvet, I., Malcus, C., Méritet, J., Lim, A., Crow, Y. J., Fabien, N., Ménétrier-Caux, C., de Villartay, J., Walzer, T., Belot, A. 2015; 135 (6): 1578-88 e5

    Abstract

    PRKDC encodes for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a kinase that forms part of a complex (DNA-dependent protein kinase [DNA-PK]) crucial for DNA double-strand break repair and V(D)J recombination. In mice DNA-PK also interacts with the transcription factor autoimmune regulator (AIRE) to promote central T-cell tolerance.We sought to understand the causes of an inflammatory disease with granuloma and autoimmunity associated with decreasing T- and B-cell counts over time that had been diagnosed in 2 unrelated patients.Genetic, molecular, and functional analyses were performed to characterize an inflammatory disease evocative of a combined immunodeficiency.We identified PRKDC mutations in both patients. These patients exhibited a defect in DNA double-strand break repair and V(D)J recombination. Whole-blood mRNA analysis revealed a strong interferon signature. On activation, memory T cells displayed a skewed cytokine response typical of TH2 and TH1 but not TH17. Moreover, mutated DNA-PKcs did not promote AIRE-dependent transcription of peripheral tissue antigens in vitro. The latter defect correlated in vivo with production of anti-calcium-sensing receptor autoantibodies, which are typically found in AIRE-deficient patients. In addition, 9 months after bone marrow transplantation, patient 1 had Hashimoto thyroiditis, suggesting that organ-specific autoimmunity might be linked to nonhematopoietic cells, such as AIRE-expressing thymic epithelial cells.Deficiency of DNA-PKcs, a key AIRE partner, can present as an inflammatory disease with organ-specific autoimmunity, suggesting a role for DNA-PKcs in regulating autoimmune responses and maintaining AIRE-dependent tolerance in human subjects.

    View details for DOI 10.1016/j.jaci.2015.01.040

    View details for PubMedID 25842288

  • Review of Environmental Impact on the Epigenetic Regulation of Atopic Diseases CURRENT ALLERGY AND ASTHMA REPORTS Sabounchi, S., Bollyky, J., Nadeau, K. 2015; 15 (6)

    View details for DOI 10.1007/s11882-015-0533-1

    View details for Web of Science ID 000357428700004

    View details for PubMedID 26141578

  • PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Mathieu, A., Verronese, E., Rice, G. I., Fouyssac, F., Bertrand, Y., Picard, C., Chansel, M., Walter, J. E., Notarangelo, L. D., Butte, M. J., Nadeau, K. C., Csomos, K., Chen, D. J., Chen, K., Delgado, A., Riga, C., Bardin, C., Schuetz, C., Moshous, D., Reumaux, H., Plenat, F., Phan, A., Zabot, M., Balme, B., Viel, S., Bienvenu, J., Cochat, P., van der Burg, M., Caux, C., Kemp, E. H., Rouvet, I., Malcus, C., Meritet, J., Lim, A., Crow, Y. J., Fabien, N., Menetrier-Caux, C., de Villartay, J., Walzer, T., Belot, A. 2015; 135 (6): 1578-U294

    View details for DOI 10.1016/j.jaci.2015.01.040

    View details for Web of Science ID 000355933400021

    View details for PubMedID 25842288

  • Review of Environmental Impact on the Epigenetic Regulation of Atopic Diseases. Current allergy and asthma reports Sabounchi, S., Bollyky, J., Nadeau, K. 2015; 15 (6): 33-?

    Abstract

    There has been significant increase in the prevalence of atopy over the past decade that cannot be explained by genetic predisposition. Environmental factors including nutrition, the uterine environment, and lifestyle factors are known to play a role in gene expression through epigenetic modifications. In this article, we review the literature on the environmental impact on epigenetic modulation of atopic diseases including asthma, food allergy, eczema, and allergic rhinitis. Recent public release of epigenomic data for hundreds of human tissues provides a powerful resource for further investigation of the molecular basis of atopic diseases.

    View details for DOI 10.1007/s11882-015-0533-1

    View details for PubMedID 26141578

  • Ambient polycyclic aromatic hydrocarbons and pulmonary function in children JOURNAL OF EXPOSURE SCIENCE AND ENVIRONMENTAL EPIDEMIOLOGY Padula, A. M., Balmes, J. R., Eisen, E. A., Mann, J., Noth, E. M., Lurmann, F. W., Pratt, B., Tager, I. B., Nadeau, K., Hammond, S. K. 2015; 25 (3): 295-302

    Abstract

    Few studies have examined the relationship between ambient polycyclic aromatic hydrocarbons (PAHs) and pulmonary function in children. Major sources include vehicular emissions, home heating, wildland fires, agricultural burning, and power plants. PAHs are an important component of fine particulate matter that has been linked to respiratory health. This cross-sectional study examines the relationship between estimated individual exposures to the sum of PAHs with 4, 5, or 6 rings (PAH456) and pulmonary function tests (forced expiratory volume in one second (FEV1) and forced expiratory flow between 25% and 75% of vital capacity) in asthmatic and non-asthmatic children. We applied land-use regression to estimate individual exposures to ambient PAHs for averaging periods ranging from 1 week to 1 year. We used linear regression to estimate the relationship between exposure to PAH456 with pre- and postbronchodilator pulmonary function tests in children in Fresno, California (N=297). Among non-asthmatics, there was a statistically significant association between PAH456 during the previous 3 months, 6 months, and 1 year and postbronchodilator FEV1. The magnitude of the association increased with the length of the averaging period ranging from 60 to 110 ml decrease in FEV1 for each 1 ng/m(3) increase in PAH456. There were no associations with PAH456 observed among asthmatic children. We identified an association between annual PAHs and chronic pulmonary function in children without asthma. Additional studies are needed to further explore the association between exposure to PAHs and pulmonary function, especially with regard to differential effects between asthmatic and non-asthmatic children.Journal of Exposure Science and Environmental Epidemiology advance online publication, 18 June 2014; doi:10.1038/jes.2014.42.

    View details for DOI 10.1038/jes.2014.42

    View details for Web of Science ID 000353405500009

    View details for PubMedID 24938508

  • Intravenous anti-IL-13 mAb QAX576 for the treatment of eosinophilic esophagitis. journal of allergy and clinical immunology Rothenberg, M. E., Wen, T., Greenberg, A., Alpan, O., Enav, B., Hirano, I., Nadeau, K., Kaiser, S., Peters, T., Perez, A., Jones, I., Arm, J. P., Strieter, R. M., Sabo, R., Gunawardena, K. A. 2015; 135 (2): 500-507

    Abstract

    Eosinophilic esophagitis (EoE) is a chronic allergic disease with limited treatment options.We evaluated QAX576, an mAb against IL-13, in the treatment of patients with EoE.Patients (18-50 years) with proton pump inhibitor-resistant esophageal eosinophilia received intravenous QAX576 (6 mg/kg) or placebo (2:1) at weeks 0, 4, and 8 and were followed for 6 months. The primary end point was the responder rate for a greater than 75% decrease in peak eosinophil counts at week 12. Efficacy was to be declared if the lower 90% confidence limit for the proportion of responders on QAX576 was 35% or greater. Secondary end points included changes in esophageal eosinophil counts, symptoms assessed by questionnaire scores, and quantification of a series of biomarkers.Twenty-three patients completed the study up to week 12, and 18 continued to the end of the study. For the proximal and distal esophageal biopsies combined, the responder rate was 12.5% (90% confidence limit, 1% to 43%) with placebo, compared to 40.0% (90% confidence limit, 22% to 61%) with QAX576. Although the primary end point was not met, the mean esophageal eosinophil count decreased by 60% with QAX576 versus an increase of 23% with placebo (P = .004), and the decrease was sustained up to 6 months. There was a trend for improved symptoms, particularly dysphagia. QAX576 improved expression of EoE-relevant esophageal transcripts, including eotaxin-3, periostin, and markers of mast cells and barrier function, for up to 6 months after treatment. QAX576 was well tolerated.QAX576 significantly improved intraepithelial esophageal eosinophil counts and dysregulated esophageal disease-related transcripts in adults with EoE in a sustained manner.

    View details for DOI 10.1016/j.jaci.2014.07.049

    View details for PubMedID 25226850

  • Genome-wide association study identifies peanut allergy-specific loci and evidence of epigenetic mediation in US children NATURE COMMUNICATIONS Hong, X., Hao, K., Ladd-Acosta, C., Hansen, K. D., Tsai, H., Liu, X., Xu, X., Thornton, T. A., Caruso, D., Keet, C. A., Sun, Y., Wang, G., Luo, W., Kumar, R., Fuleihan, R., Singh, A. M., Kim, J. S., Story, R. E., Gupta, R. S., Gao, P., Chen, Z., Walker, S. O., Bartell, T. R., Beaty, T. H., Fallin, M. D., Schleimer, R., Holt, P. G., Nadeau, K. C., Wood, R. A., Pongracic, J. A., Weeks, D. E., Wang, X. 2015; 6

    View details for DOI 10.1038/ncomms7304

    View details for Web of Science ID 000350290300002

    View details for PubMedID 25710614

  • The future of biologics: applications for food allergy. journal of allergy and clinical immunology Bauer, R. N., Manohar, M., Singh, A. M., Jay, D. C., Nadeau, K. C. 2015; 135 (2): 312-323

    Abstract

    Allergic diseases affect millions worldwide, with growing evidence of an increase in allergy occurrence over the past few decades. Current treatments for allergy include corticosteroids to reduce inflammation and allergen immunotherapy; however, some subjects experience treatment-resistant inflammation or adverse reactions to these treatments, and there are currently no approved therapeutics for the treatment of food allergy. There is a dire need for new therapeutic approaches for patients with poorly controlled atopic diseases and a need to improve the safety and effectiveness of allergen immunotherapy. Improved understanding of allergy through animal models and clinical trials has unveiled potential targets for new therapies, leading to the development of several biologics to treat allergic diseases. This review focuses on the mechanisms that contribute to allergy, with an emphasis on future targets for biologics for the treatment of food allergy. These biologics include immunotherapy with novel anti-IgE antibodies and analogs, small-molecule inhibitors of cell signaling, anti-type 2 cytokine mAbs, and TH1-promoting adjuvants.

    View details for DOI 10.1016/j.jaci.2014.12.1908

    View details for PubMedID 25662303

  • The future of biologics: Applications for food allergy JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Bauer, R. N., Manohar, M., Singh, A. M., Jay, D. C., Nadeau, K. C. 2015; 135 (2): 312-323
  • Human in vitro induced T regulatory cells and memory T cells share common demethylation of specific FOXP3 promoter region. Clinical and translational allergy Bégin, P., Schulze, J., Baron, U., Olek, S., Bauer, R. N., Passerini, L., Baccheta, R., Nadeau, K. C. 2015; 5: 35-?

    Abstract

    The FOXP3 gene is the master regulator for T regulatory cells and is under tight DNA methylation control at the Treg specific demethylated region (TSDR) in its first intron. This said, methylation of its promoter region, the significance of which is unknown, has also been associated with various immune-related disease states such as asthma, food allergy, auto-immunity and cancer. Here, we used induced T regulatory cells (iTreg) as a target cell population to identify candidate hypomethylated CpG sites in the FOXP3 gene promoter to design a DNA methylation quantitative assay for this region.Three CpG sites at the promoter region showed clear demethylation pattern associated with high FOXP3 expression after activation in presence of TGFβ and were selected as primary targets to design methylation-dependent RT-PCR primers and probes. We then examined the methylation of this 'inducible-promoter-demethylated-region' (IPDR) in various FOXP3+ T cell subsets. Both naïve and memory thymic-derived Treg cells were found to be fully demethylated at both the IPDR and TSDR. Interestingly, in addition to iTregs, both CD25- and CD25(lo) conventional memory CD4+CD45RA- T cells displayed a high fraction of IPDR demethylated cells in absence of TSDR demethylation.This implies that the fraction of memory T cells should be taken in account when interpreting FOXP3 promoter methylation results from clinical studies. This approach, which is available for testing in clinical samples could have diagnostic and prognostic value in patients with immune or auto-inflammatory diseases.

    View details for DOI 10.1186/s13601-015-0079-2

    View details for PubMedID 26500760

    View details for PubMedCentralID PMC4617722

  • The evolution of allergen and non-specific immunotherapy: past achievements, current applications and future outlook EXPERT REVIEW OF CLINICAL IMMUNOLOGY Pajno, G. B., Nadeau, K. C., Passalacqua, G., Caminiti, L., Hobson, B., Jay, D. C., Arasi, S., Chiera, F., Salzano, G. 2015; 11 (1): 141-154

    Abstract

    Recent epidemiological studies estimated that more than 30% of European suffer from allergic rhinitis or conjunctivitis, while up to 20% suffer from asthma and 15% from allergic skin conditions, while for many other regions the prevalence is increasing. Allergen immunotherapy represents the only available treatment that can modify the allergic disease process, and thus is worth considering as a treatment in affected individuals. A beneficial effect of allergen immunotherapy has been shown in both adults and children affected by allergic rhinitis, allergic conjunctivitis, allergic asthma and hymenoptera venom allergy. The present study represents an overview on allergen immunotherapy, focusing on the principal aspects of the use of immunotherapy in the past, its recent clinical applications and future outlook.

    View details for DOI 10.1586/1744666X.2015.977260

    View details for Web of Science ID 000346760700011

    View details for PubMedID 25454510

  • Genome-wide association study identifies peanut allergy-specific loci and evidence of epigenetic mediation in US children. Nature communications Hong, X., Hao, K., Ladd-Acosta, C., Hansen, K. D., Tsai, H., Liu, X., Xu, X., Thornton, T. A., Caruso, D., Keet, C. A., Sun, Y., Wang, G., Luo, W., Kumar, R., Fuleihan, R., Singh, A. M., Kim, J. S., Story, R. E., Gupta, R. S., Gao, P., Chen, Z., Walker, S. O., Bartell, T. R., Beaty, T. H., Fallin, M. D., Schleimer, R., Holt, P. G., Nadeau, K. C., Wood, R. A., Pongracic, J. A., Weeks, D. E., Wang, X. 2015; 6: 6304-?

    Abstract

    Food allergy (FA) affects 2%-10% of US children and is a growing clinical and public health problem. Here we conduct the first genome-wide association study of well-defined FA, including specific subtypes (peanut, milk and egg) in 2,759 US participants (1,315 children and 1,444 parents) from the Chicago Food Allergy Study, and identify peanut allergy (PA)-specific loci in the HLA-DR and -DQ gene region at 6p21.32, tagged by rs7192 (P=5.5 × 10(-8)) and rs9275596 (P=6.8 × 10(-10)), in 2,197 participants of European ancestry. We replicate these associations in an independent sample of European ancestry. These associations are further supported by meta-analyses across the discovery and replication samples. Both single-nucleotide polymorphisms (SNPs) are associated with differential DNA methylation levels at multiple CpG sites (P<5 × 10(-8)), and differential DNA methylation of the HLA-DQB1 and HLA-DRB1 genes partially mediate the identified SNP-PA associations. This study suggests that the HLA-DR and -DQ gene region probably poses significant genetic risk for PA.

    View details for DOI 10.1038/ncomms7304

    View details for PubMedID 25710614

  • Childhood exposure to ambient polycyclic aromatic hydrocarbons is linked to epigenetic modifications and impaired systemic immunity in T cells. Clinical and experimental allergy Hew, K. M., WALKER, A. I., Kohli, A., Garcia, M., Syed, A., McDonald-Hyman, C., Noth, E. M., Mann, J. K., Pratt, B., Balmes, J., Hammond, S. K., Eisen, E. A., Nadeau, K. C. 2015; 45 (1): 238-248

    Abstract

    Evidence suggests that exposure to polycyclic aromatic hydrocarbons (PAHs) increases atopy; it is unclear how PAH exposure is linked to increased severity of atopic diseases.We hypothesized that ambient PAH exposure is linked to impairment of immunity in atopic children (defined as children with asthma and/or allergic rhinitis) from Fresno, California, an area with elevated ambient PAHs.We recruited 256 subjects from Fresno, CA. Ambient PAH concentrations (ng/m(3) ) were measured using a spatial-temporal regression model over multiple time periods. Asthma diagnosis was determined by current NHLBI criteria. Phenotyping and functional immune measurements were performed from isolated cells. For epigenetic measurements, DNA was isolated and pyrosequenced.We show that higher average PAH exposure was significantly associated with impaired Treg function and increased methylation in the forkhead box protein 3 (FOXP3) locus (P < 0.05), conditional on atopic status. These epigenetic modifications were significantly linked to differential protein expression of FOXP3 (P < 0.001). Methylation was associated with cellular functional changes, specifically Treg dysfunction, and an increase in total plasma IgE levels. Protein expression of IL-10 decreased and IFN-γ increased as the extent of PAH exposure increased. The strength of the associations generally increased as the time window for average PAH exposure increased from 24 hr to 1 year, suggesting more of a chronic response. Significant associations with chronic PAH exposure and immune outcomes were also observed in subjects with allergic rhinitis.Collectively, these results demonstrate that increased ambient PAH exposure is associated with impaired systemic immunity and epigenetic modifications in a key locus involved in atopy: FOXP3, with a higher impact on atopic children. The results suggest that increased atopic clinical symptoms in children could be linked to increased PAH exposure in air pollution.

    View details for DOI 10.1111/cea.12377

    View details for PubMedID 25048800

  • Exome sequencing and genome-wide copy number variant mapping reveal novel associations with sensorineural hereditary hearing loss BMC GENOMICS Haraksingh, R. R., Jahanbani, F., Rodriguez-Paris, J., Gelernter, J., Nadeau, K. C., Oghalai, J. S., Schrijver, I., Snyder, M. P. 2014; 15
  • In utero arsenic exposure and fetal immune repertoire in a US pregnancy cohort CLINICAL IMMUNOLOGY Nadeau, K. C., Li, Z., Farzan, S., Koestler, D., Robbins, D., Fei, D. L., Malipatlolla, M., Maecker, H., Enelow, R., Korrick, S., Karagas, M. R. 2014; 155 (2): 188-197

    Abstract

    Arsenic has wide-ranging effects on human health and there is evidence that it alters the immune response by influencing CD4+/CD8+ T cell ratios, IL-2 cytokine levels, and the expression of immune-response genes. We investigated the impact of in utero environmental arsenic exposure on immune development and function in newborns participating in a pregnancy cohort in New Hampshire, U.S., where arsenic levels have exceeded the current EPA maximum contaminant level of 10 μg/L. Our results showed that maternal urinary arsenic concentrations were inversely related to absolute total CD45RA+ CD4+ cord blood CD69+ T cell counts (N=116, p=0.04) and positively associated with CD45RA+ CD69- CD294+ cell counts (p=0.01). In placental samples (N=70), higher in utero urinary arsenic concentrations were positively associated with the expression of IL1β (p=0.03). These data provide evidence that relatively low-level arsenic exposure in utero may alter the fetal immune system and lead to immune dysregulation.

    View details for DOI 10.1016/j.clim.2014.09.004

    View details for Web of Science ID 000346114300004

    View details for PubMedID 25229165

  • Two year effects of food allergen immunotherapy on quality of life in caregivers of children with food allergies ALLERGY ASTHMA AND CLINICAL IMMUNOLOGY Arasi, S., Otani, I. M., Klingbeil, E., Begin, P., Kearney, C., Dominguez, T. L., Block, W. M., O'Riordan, G., Nadeau, K. C. 2014; 10
  • Twin and family studies reveal strong environmental and weaker genetic cues explaining heritability of eosinophilic esophagitis JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Alexander, E. S., Martin, L. J., Collins, M. H., Kottyan, L. C., Sucharew, H., He, H., Mukkada, V. A., Succop, P. A., Abonia, J. P., Foote, H., Eby, M. D., Grotjan, T. M., Greenler, A. J., Dellon, E. S., Demain, J. G., Furuta, G. T., Gurian, L. E., Harley, J. B., Hopp, R. J., Kagalwalla, A., Kaul, A., Nadeau, K. C., Noel, R. J., Putnam, P. E., von Tiehl, K. F., Rothenberg, M. E. 2014; 134 (5): 1084-?
  • GWAS identifies four novel eosinophilic esophagitis loci NATURE COMMUNICATIONS Sleiman, P. M., Wang, M., Cianferoni, A., Aceves, S., Gonsalves, N., Nadeau, K., Bredenoord, A. J., Furuta, G. T., Spergel, J. M., Hakonarson, H. 2014; 5

    Abstract

    Eosinophilic esophagitis (EoE) is an allergic disorder characterized by infiltration of the oesophagus with eosinophils. We had previously reported association of the TSLP/WDR36 locus with EoE. Here we report genome-wide significant associations at four additional loci; c11orf30 and STAT6, which have been previously associated with both atopic and autoimmune diseases, and two EoE-specific loci, ANKRD27 that regulates the trafficking of melanogenic enzymes to epidermal melanocytes and CAPN14, that encodes a calpain whose expression is highly enriched in the oesophagus. The identification of five EoE loci, not only expands our aetiological understanding of the disease but may also represent new therapeutic targets to treat the most debilitating aspect of EoE, oesophageal inflammation and remodelling.

    View details for DOI 10.1038/ncomms6593

    View details for Web of Science ID 000346082000003

    View details for PubMedID 25407941

  • Food allergy: A practice parameter update-2014 JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Sampson, H. A., Aceves, S., Bock, S. A., James, J., Jones, S., Lang, D., Nadeau, K., Nowak-Wegrzyn, A., Oppenheimer, J., Perry, T. T., Randolph, C., Sicherer, S. H., Simon, R. A., Vickery, B. P., Wood, R. 2014; 134 (5): 1016-?

    Abstract

    This parameter was developed by the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma & Immunology (JCAAI). The AAAAI and the ACAAI have jointly accepted responsibility for establishing "Food Allergy: A practice parameter update-2014." This is a complete and comprehensive document at the current time. The medical environment is a changing one, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, ACAAI, and JCAAI. These parameters are not designed for use by pharmaceutical companies in drug promotion.

    View details for DOI 10.1016/j.jaci.2014.05.013

    View details for Web of Science ID 000344938900004

    View details for PubMedID 25174862

  • Immune Mechanisms of Sublingual Immunotherapy CURRENT ALLERGY AND ASTHMA REPORTS Jay, D. C., Nadeau, K. C. 2014; 14 (11)

    Abstract

    Sublingual immunotherapy (SLIT) is a well-established allergen-specific immunotherapy and a safe and effective strategy to reorient inappropriate immune responses in allergic patients. SLIT takes advantage of the tolerogenic environment of the oral mucosa to promote tolerance to the allergen. Several clinical studies have investigated the complex interplay of innate and adaptive immune responses that SLIT exploits. The oral immune system is composed of tolerogenic dendritic cells that, following uptake of allergen during SLIT, support the differentiation of T helper cell type 1 (Th1) and the induction of IL-10-producing regulatory T cells. Following SLIT, allergic disease-promoting T helper cell type 2 (Th2) responses shift to a Th1 inflammatory response, and IL-10 and transforming growth factor (TGF)-β production by regulatory T cells and tolerogenic dendritic cells suppress allergen-specific T cell responses. These immune changes occur both in the sublingual mucosa and in the periphery of a patient following SLIT. SLIT also promotes the synthesis of allergen-specific IgG and IgA antibodies that block allergen-IgE complex formation and binding to inflammatory cells, thus encouraging an anti-inflammatory environment. Several of these revealing findings have also paved the way for the identification of biomarkers of the clinical efficacy of SLIT. This review presents the emerging elucidation of the immune mechanisms mediated by SLIT.

    View details for DOI 10.1007/s11882-014-0473-1

    View details for Web of Science ID 000343644500004

    View details for PubMedID 25195100

  • Lessons learned from mice and man: Mimicking human allergy through mouse models CLINICAL IMMUNOLOGY Graham, M. T., Nadeau, K. C. 2014; 155 (1): 1-16
  • Long-term Sinonasal Outcomes of Aspirin Desensitization in Aspirin Exacerbated Respiratory Disease OTOLARYNGOLOGY-HEAD AND NECK SURGERY Cho, K., Soudry, E., Psaltis, A. J., Nadeau, K. C., McGhee, S. A., Nayak, J. V., Hwang, P. H. 2014; 151 (4): 575-581
  • Abdominal and general adiposity and level of asthma control in adults with uncontrolled asthma. Annals of the American Thoracic Society Lv, N., Xiao, L., Camargo, C. A., Wilson, S. R., Buist, A. S., Strub, P., Nadeau, K. C., Ma, J. 2014; 11 (8): 1218-1224

    Abstract

    Abdominal adiposity may be an important risk factor for uncontrolled asthma in adults, controlling for general obesity. Whether the relationship, if present, is explained by other factors (e.g., asthma onset age, sex, and/or coexisting conditions) is unclear.To examine whether clinically applicable anthropometric measures of abdominal adiposity--waist circumference and waist-to-height ratio (WHtR)--are related to poorer asthma control in adults with uncontrolled asthma controlling for body mass index (BMI), and whether the relationship (if present) is explained by gastroesophageal reflux disorder (GERD), sleep quality, or obstructive sleep apnea (OSA) or differs by age of asthma onset or sex.Patients aged 18 to 70 years with uncontrolled asthma (n = 90) participated in a 6-month randomized clinical trial.Baseline measures included sociodemographics, standardized anthropometrics, Asthma Control Test (ACT), GERD Symptom Assessment Scale, Pittsburgh Sleep Quality Index, and Berlin Questionnaire for Sleep Apnea. Participants (mean [SD] age, 52 [12] yr) were racially and ethnically diverse, 67% women, and 69% overweight or obese, and 71% reported their age of asthma onset was 12 years or older. Participants had uncontrolled asthma (mean [SD] ACT score, 14.9 [3.7]) and low GERD symptoms score (0.6 [0.4]); 67% reported poor sleep quality, and 42% had a high OSA risk. General linear regression results showed that worse ACT scores were significantly associated with every SD increase in waist circumference (β = -1.03; 95% confidence interval [CI], -1.96 to -0.16; P = 0.02) and waist-to-height ratio (β = -1.16; 95% CI, -2.00 to -0.33; P = 0.008), controlling for sociodemographics. Waist-to-height ratio remained correlated with ACT (β = -2.30; 95% CI, -4.16 to -0.45; P = 0.02) after further adjusting for BMI. The BMI-controlled relationship between WHtR and ACT did not differ by age of asthma onset or sex (P > 0.05 for interactions) and persisted after additional adjustment for GERD, sleep quality, or OSA scores. Poor sleep quality was associated with worse ACT scores (β = -0.87; 95% CI, -1.71 to -0.03; P = 0.045) controlling for waist-to-height ratio, BMI, and sociodemographics.Abdominal adiposity by waist-to-height ratio and poor sleep quality correlated with poorer asthma control in adults with uncontrolled asthma, after controlling for BMI and sociodemographics. These results warrant replication in larger studies of diverse populations. Clinical trial registered with www.clinicaltrials.gov (NCT 01725945).

    View details for DOI 10.1513/AnnalsATS.201405-214OC

    View details for PubMedID 25343191

  • Novel protocol including liver biopsy to identify and treat CD8+ T-cell predominant acute hepatitis and liver failure. Pediatric transplantation McKenzie, R. B., Berquist, W. E., Nadeau, K. C., Louie, C. Y., Chen, S. F., Sibley, R. K., Glader, B. E., Wong, W. B., Hofmann, L. V., Esquivel, C. O., Cox, K. L. 2014; 18 (5): 503-509

    Abstract

    In the majority of children with ALF, the etiology is unknown and liver transplantation is often needed for survival. A patient case prompted us to consider that immune dysregulation may be the cause of indeterminate acute hepatitis and liver failure in children. Our study includes nine pediatric patients treated under a multidisciplinary clinical protocol to identify and treat immune-mediated acute liver injury. Patients with evidence of inflammation and no active infection on biopsy received treatment with intravenous immune globulin and methylprednisolone. Seven patients had at least one positive immune marker before or after treatment. All patients had a CD8+ T-cell predominant liver injury that completely or partially responded to immune therapy. Five of the nine patients recovered liver function and did not require liver transplantation. Three of these patients subsequently developed bone marrow failure and were treated with either immunosuppression or stem cell transplant. This series highlights the importance of this tissue-based approach to diagnosis and treatment that may improve transplant-free survival. Further research is necessary to better characterize the immune injury and to predict the subset of patients at risk for bone marrow failure who may benefit from earlier and stronger immunosuppressive therapy.

    View details for DOI 10.1111/petr.12296

    View details for PubMedID 24930635

  • The Potential of Anti-IgE in Food Allergy Therapy. Current treatment options in allergy Manohar, M., Nadeau, K. C. 2014; 1 (2): 145-156

    View details for PubMedID 25419508

  • Epigenetic regulation of asthma and allergic disease ALLERGY ASTHMA AND CLINICAL IMMUNOLOGY Begin, P., Nadeau, K. C. 2014; 10

    Abstract

    Epigenetics of asthma and allergic disease is a field that has expanded greatly in the last decade. Previously thought only in terms of cell differentiation, it is now evident the epigenetics regulate many processes. With T cell activation, commitment toward an allergic phenotype is tightly regulated by DNA methylation and histone modifications at the Th2 locus control region. When normal epigenetic control is disturbed, either experimentally or by environmental exposures, Th1/Th2 balance can be affected. Epigenetic marks are not only transferred to daughter cells with cell replication but they can also be inherited through generations. In animal models, with constant environmental pressure, epigenetically determined phenotypes are amplified through generations and can last up to 2 generations after the environment is back to normal. In this review on the epigenetic regulation of asthma and allergic diseases we review basic epigenetic mechanisms and discuss the epigenetic control of Th2 cells. We then cover the transgenerational inheritance model of epigenetic traits and discuss how this could relate the amplification of asthma and allergic disease prevalence and severity through the last decades. Finally, we discuss recent epigenetic association studies for allergic phenotypes and related environmental risk factors as well as potential underlying mechanisms for these associations.

    View details for DOI 10.1186/1710-1492-10-27

    View details for Web of Science ID 000337487700001

    View details for PubMedID 24932182

  • Regulatory T cells and their roles in immune dysregulation and allergy. Immunologic research Pellerin, L., Jenks, J. A., Bégin, P., Bacchetta, R., Nadeau, K. C. 2014; 58 (2-3): 358-368

    Abstract

    The main function of the immune system is to fight off potential infections, but also to maintain its activity below a level that would trigger self-reactivity. Regulatory T cells (Tregs) such as forkhead box P3(+) (FOXP3) Tregs and type 1 regulatory T cells (Tr1) play an essential role in this active process, using several distinct suppressive mechanisms. A wide range of pathologies have been associated with altered Treg cell function. This is best exemplified by the impact of mutations of genes essential for Treg function and the associated autoimmune syndromes. This review summarizes the main features of different subtypes of Tregs and focuses on the clinical implications of their altered function in human studies. More specifically, we discuss abnormalities affecting FOXP3(+) Tregs and Tr1 cells that will lead to autoimmune manifestations and/or allergic reactions, and the potential therapeutic use of Tregs.

    View details for DOI 10.1007/s12026-014-8512-5

    View details for PubMedID 24781194

  • Polycyclic aromatic hydrocarbons, tobacco smoke, and epigenetic remodeling in asthma. Immunologic research Klingbeil, E. C., Hew, K. M., Nygaard, U. C., Nadeau, K. C. 2014; 58 (2-3): 369-373

    Abstract

    Environmental determinants including aerosolized pollutants such as polycyclic aromatic hydrocarbons (PAHs) and tobacco smoke have been associated with exacerbation and increased incidence of asthma. The influence of aerosolized pollutants on the development of immune dysfunction in asthmatics has been suggested to be mediated through epigenetic remodeling. Genome accessibility and transcription are regulated primarily through DNA methylation, histone modification, and microRNA transcript silencing. Epigenetic remodeling has been shown in studies to be associated with Th2 polarization and associated cytokine and chemokine regulation in the development of asthma. This review will present evidence for the contribution of the aerosolized pollutants PAH and environmental tobacco smoke to epigenetic remodeling in asthma.

    View details for DOI 10.1007/s12026-014-8508-1

    View details for PubMedID 24760221

  • Peanut oral immunotherapy results in increased antigen-induced regulatory T-cell function and hypomethylation of forkhead box protein 3 (FOXP3). journal of allergy and clinical immunology Syed, A., Garcia, M. A., Lyu, S., Bucayu, R., Kohli, A., Ishida, S., Berglund, J. P., Tsai, M., Maecker, H., O'Riordan, G., Galli, S. J., Nadeau, K. C. 2014; 133 (2): 500-510

    Abstract

    The mechanisms contributing to clinical immune tolerance remain incompletely understood. This study provides evidence for specific immune mechanisms that are associated with a model of operationally defined clinical tolerance.Our overall objective was to study laboratory changes associated with clinical immune tolerance in antigen-induced T cells, basophils, and antibodies in subjects undergoing oral immunotherapy (OIT) for peanut allergy.In a phase 1 single-site study, we studied participants (n = 23) undergoing peanut OIT and compared them with age-matched allergic control subjects (n = 20) undergoing standard of care (abstaining from peanut) for 24 months. Participants were operationally defined as clinically immune tolerant (IT) if they had no detectable allergic reactions to a peanut oral food challenge after 3 months of therapy withdrawal (IT, n = 7), whereas those who had an allergic reaction were categorized as nontolerant (NT; n = 13).Antibody and basophil activation measurements did not statistically differentiate between NT versus IT participants. However, T-cell function and demethylation of forkhead box protein 3 (FOXP3) CpG sites in antigen-induced regulatory T cells were significantly different between IT versus NT participants. When IT participants were withdrawn from peanut therapy for an additional 3 months (total of 6 months), only 3 participants remained classified as IT participants, and 4 participants regained sensitivity along with increased methylation of FOXP3 CpG sites in antigen-induced regulatory T cells.In summary, modifications at the DNA level of antigen-induced T-cell subsets might be predictive of a state of operationally defined clinical immune tolerance during peanut OIT.

    View details for DOI 10.1016/j.jaci.2013.12.1037

    View details for PubMedID 24636474

  • Peanut oral immunotherapy results in increased antigen-induced regulatory T-cell function and hypomethylation of forkhead box protein 3 (FOXP3). journal of allergy and clinical immunology Syed, A., Garcia, M. A., Lyu, S., Bucayu, R., Kohli, A., Ishida, S., Berglund, J. P., Tsai, M., Maecker, H., O'Riordan, G., Galli, S. J., Nadeau, K. C. 2014; 133 (2): 500-510 e11

    View details for DOI 10.1016/j.jaci.2013.12.1037

    View details for PubMedID 24636474

  • Identification of STAT5A and STAT5B Target Genes in Human T Cells. PloS one Kanai, T., Seki, S., Jenks, J. A., Kohli, A., Kawli, T., Martin, D. P., Snyder, M., Bacchetta, R., Nadeau, K. C. 2014; 9 (1)

    View details for DOI 10.1371/journal.pone.0086790

    View details for PubMedID 24497979

  • Identification of STAT5A and STAT5B target genes in human T cells. PloS one Kanai, T., Seki, S., Jenks, J. A., Kohli, A., Kawli, T., Martin, D. P., Snyder, M., Bacchetta, R., Nadeau, K. C. 2014; 9 (1)

    Abstract

    Signal transducer and activator of transcription (STAT) comprises a family of universal transcription factors that help cells sense and respond to environmental signals. STAT5 refers to two highly related proteins, STAT5A and STAT5B, with critical function: their complete deficiency is lethal in mice; in humans, STAT5B deficiency alone leads to endocrine and immunological problems, while STAT5A deficiency has not been reported. STAT5A and STAT5B show peptide sequence similarities greater than 90%, but subtle structural differences suggest possible non-redundant roles in gene regulation. However, these roles remain unclear in humans. We applied chromatin immunoprecipitation followed by DNA sequencing using human CD4(+) T cells to detect candidate genes regulated by STAT5A and/or STAT5B, and quantitative-PCR in STAT5A or STAT5B knock-down (KD) human CD4(+) T cells to validate the findings. Our data show STAT5A and STAT5B play redundant roles in cell proliferation and apoptosis via SGK1 interaction. Interestingly, we found a novel, unique role for STAT5A in binding to genes involved in neural development and function (NDRG1, DNAJC6, and SSH2), while STAT5B appears to play a distinct role in T cell development and function via DOCK8, SNX9, FOXP3 and IL2RA binding. Our results also suggest that one or more co-activators for STAT5A and/or STAT5B may play important roles in establishing different binding abilities and gene regulation behaviors. The new identification of these genes regulated by STAT5A and/or STAT5B has major implications for understanding the pathophysiology of cancer progression, neural disorders, and immune abnormalities.

    View details for DOI 10.1371/journal.pone.0086790

    View details for PubMedID 24497979

  • Multiple-allergen oral immunotherapy improves quality of life in caregivers of food-allergic pediatric subjects. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology Otani, I. M., Bégin, P., Kearney, C., Dominguez, T. L., Mehrotra, A., Bacal, L. R., Wilson, S., Nadeau, K. 2014; 10 (1): 25-?

    Abstract

    Food allergy (FA) negatively affects quality of life in caregivers of food-allergic children, imposing a psychosocial and economic burden. Oral immunotherapy (OIT) is a promising investigational therapy for FA. However, OIT can be a source of anxiety as it carries risk for allergic reactions. The effect of OIT with multiple food allergens (mOIT) on FA-specific health-related quality of life (HRQL) has never been studied in participants with multiple, severe food allergies. This study is the first to investigate the effects of mOIT on FA-related HRQL in caregivers of pediatric subjects.Caregiver HRQL was assessed using a validated Food Allergy Quality of Life - Parental Burden (FAQL-PB) Questionnaire (J Allergy Clin Immunol 114(5):1159-1163, 2004). Parents of participants in two single-center Phase I clinical trials receiving mOIT (n = 29) or rush mOIT with anti-IgE (omalizumab) pre-treatment (n = 11) completed the FAQL-PB prior to study intervention and at 2 follow-up time-points (6 months and 18 months). Parents of subjects not receiving OIT (control group, n = 10) completed the FAQL-PB for the same time-points.HRQL improved with clinical (change < -0.5) and statistical (p < 0.05) significance in the mOIT group (baseline mean 3.9, 95% CI 3.4-4.4; 6-month follow-up mean 2.5, 95% CI 2.0-3.0; 18-month follow-up mean 1.8, 95% CI 1.4-2.1) and rush mOIT group (baseline mean 3.9, 95% CI 3.1-4.7; 6-month follow-up mean 1.7, 95% CI 0.9-2.6; 18-month follow-up mean 1.3, 95% CI 0.3-2.4). HRQL scores did not significantly change in the control group (n = 10).Multi-allergen OIT with or without omalizumab leads to improvement in caregiver HRQL, suggesting that mOIT can help relieve the psychosocial and economic burden FA imposes on caregivers of food-allergic children.

    View details for DOI 10.1186/1710-1492-10-25

    View details for PubMedID 24860608

  • Safety and feasibility of oral immunotherapy to multiple allergens for food allergy. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology Bégin, P., Winterroth, L. C., Dominguez, T., Wilson, S. P., Bacal, L., Mehrotra, A., Kausch, B., Trela, A., Hoyte, E., O'Riordan, G., Seki, S., Blakemore, A., Woch, M., Hamilton, R. G., Nadeau, K. C. 2014; 10 (1): 1-?

    Abstract

    Thirty percent of children with food allergy are allergic to more than one food. Previous studies on oral immunotherapy (OIT) for food allergy have focused on the administration of a single allergen at the time. This study aimed at evaluating the safety of a modified OIT protocol using multiple foods at one time.Participants underwent double-blind placebo-controlled food challenges (DBPCFC) up to a cumulative dose of 182 mg of food protein to peanut followed by other nuts, sesame, dairy or egg. Those meeting inclusion criteria for peanut only were started on single-allergen OIT while those with additional allergies had up to 5 foods included in their OIT mix. Reactions during dose escalations and home dosing were recorded in a symptom diary.Forty participants met inclusion criteria on peanut DBPCFC. Of these, 15 were mono-allergic to peanut and 25 had additional food allergies. Rates of reaction per dose did not differ significantly between the two groups (median of 3.3% and 3.7% in multi and single OIT group, respectively; p = .31). In both groups, most reactions were mild but two severe reactions requiring epinephrine occurred in each group. Dose escalations progressed similarly in both groups although, per protocol design, those on multiple food took longer to reach equivalent doses per food (median +4 mo.; p < .0001).Preliminary data show oral immunotherapy using multiple food allergens simultaneously to be feasible and relatively safe when performed in a hospital setting with trained personnel. Additional, larger, randomized studies are required to continue to test safety and efficacy of multi-OIT.Clinicaltrial.gov NCT01490177.

    View details for DOI 10.1186/1710-1492-10-1

    View details for PubMedID 24428859

  • Phase 1 results of safety and tolerability in a rush oral immunotherapy protocol to multiple foods using Omalizumab. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology Bégin, P., Dominguez, T., Wilson, S. P., Bacal, L., Mehrotra, A., Kausch, B., Trela, A., Tavassoli, M., Hoyte, E., O'Riordan, G., Blakemore, A., Seki, S., Hamilton, R. G., Nadeau, K. C. 2014; 10 (1): 7-?

    Abstract

    Up to 30% of patients with food allergies have clinical reactivity to more than one food allergen. Although there is currently no cure, oral immunotherapy (OIT) is under investigation. Pilot data have shown that omalizumab may hasten the ability to tolerate over 4 g of food allergen protein.To evaluate the safety and dose tolerability of a Phase 1 Single Site OIT protocol using omalizumab to allow for a faster and safe desensitization to multiple foods simultaneously.Participants with multiple food allergies received OIT for up to 5 allergens simultaneously with omalizumab (rush mOIT). Omalizumab was administered for 8 weeks prior to and 8 weeks following the initiation of a rush mOIT schedule. Home reactions were recorded with diaries.Twenty-five (25) participants were enrolled in the protocol (median age 7 years). For each included food, participants had failed an initial double-blind placebo-controlled food challenge at a protein dose of 100 mg or less. After pre-treatment with omalizumab, 19 participants tolerated all 6 steps of the initial escalation day (up to 1250 mg of combined food proteins), requiring minimal or no rescue therapy. The remaining 6 were started on their highest tolerated dose as their initial daily home doses. Participants reported 401 reactions per 7,530 home doses (5.3%) with a median of 3.2 reactions per 100 doses. Ninety-four percent (94%) of reactions were mild. There was one severe reaction. Participants reached their maintenance dose of 4,000 mg protein per allergen at a median of 18 weeks.These phase 1 data demonstrate that rush OIT to multiple foods with 16 weeks of treatment with omalizumab could allow for a fast desensitization in subjects with multiple food allergies. Phase 2 randomized controlled trials are needed to better define safety and efficacy parameters of multi OIT experimental treatments with and without omalizumab.

    View details for DOI 10.1186/1710-1492-10-7

    View details for PubMedID 24576338

  • Oral immunotherapy for the treatment of food allergy HUMAN VACCINES & IMMUNOTHERAPEUTICS Begin, P., Chinthrajah, R. S., Nadeau, K. C. 2014; 10 (8): 2295-2302

    Abstract

    Oral immunotherapy (OIT) is an emerging new therapy for food allergy. With multiple small exploratory trials and some large randomized-controlled phase 2 trials recently published and under way, there is a clear progress and interest toward making this a treatment option for patients suffering from food allergies. However, there are still many questions to be answered and parameters to fine-tune before OIT becomes an accepted option outside of the research setting. This review covers the main milestones in the development of OIT for food allergy and further discusses important specific issues that will have direct impact on its clinical application. More specifically, previous publications showing evidence for the induction of tolerance are specifically reviewed and varying safety, tolerability and efficacy parameters from previous reports are also discussed.

    View details for DOI 10.4161/hv.29233

    View details for Web of Science ID 000344318300027

    View details for PubMedID 25424935

  • Safety and feasibility of oral immunotherapy to multiple allergens for food allergy. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology Bégin, P., Winterroth, L. C., Dominguez, T., Wilson, S. P., Bacal, L., Mehrotra, A., Kausch, B., Trela, A., Hoyte, E., O'Riordan, G., Seki, S., Blakemore, A., Woch, M., Hamilton, R. G., Nadeau, K. C. 2014; 10 (1): 1-?

    View details for DOI 10.1186/1710-1492-10-1

    View details for PubMedID 24428859

  • Phase 1 results of safety and tolerability in a rush oral immunotherapy protocol to multiple foods using Omalizumab. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology Bégin, P., Dominguez, T., Wilson, S. P., Bacal, L., Mehrotra, A., Kausch, B., Trela, A., Tavassoli, M., Hoyte, E., O'Riordan, G., Blakemore, A., Seki, S., Hamilton, R. G., Nadeau, K. C. 2014; 10 (1): 7-?

    View details for DOI 10.1186/1710-1492-10-7

    View details for PubMedID 24576338

  • Multiple-allergen oral immunotherapy improves quality of life in caregivers of food-allergic pediatric subjects. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology Otani, I. M., Bégin, P., Kearney, C., Dominguez, T. L., Mehrotra, A., Bacal, L. R., Wilson, S., Nadeau, K. 2014; 10 (1): 25-?

    View details for DOI 10.1186/1710-1492-10-25

    View details for PubMedID 24860608

  • Exome sequencing and genome-wide copy number variant mapping reveal novel associations with sensorineural hereditary hearing loss. BMC genomics Haraksingh, R. R., Jahanbani, F., Rodriguez-Paris, J., Gelernter, J., Nadeau, K. C., Oghalai, J. S., Schrijver, I., Snyder, M. P. 2014; 15: 1155-?

    Abstract

    The genetic diversity of loci and mutations underlying hereditary hearing loss is an active area of investigation. To identify loci associated with predominantly non-syndromic sensorineural hearing loss, we performed exome sequencing of families and of single probands, as well as copy number variation (CNV) mapping in a case-control cohort.Analysis of three distinct families revealed several candidate loci in two families and a single strong candidate gene, MYH7B, for hearing loss in one family. MYH7B encodes a Type II myosin, consistent with a role for cytoskeletal proteins in hearing. High-resolution genome-wide CNV analysis of 150 cases and 157 controls revealed deletions in genes known to be involved in hearing (e.g. GJB6, OTOA, and STRC, encoding connexin 30, otoancorin, and stereocilin, respectively), supporting CNV contributions to hearing loss phenotypes. Additionally, a novel region on chromosome 16 containing part of the PDXDC1 gene was found to be frequently deleted in hearing loss patients (OR = 3.91, 95% CI: 1.62-9.40, p = 1.45 x 10-7).We conclude that many known as well as novel loci and distinct types of mutations not typically tested in clinical settings can contribute to the etiology of hearing loss. Our study also demonstrates the challenges of exome sequencing and genome-wide CNV mapping for direct clinical application, and illustrates the need for functional and clinical follow-up as well as curated open-access databases.

    View details for DOI 10.1186/1471-2164-15-1155

    View details for PubMedID 25528277

  • Selective ablation of mast cells or basophils reduces peanut-induced anaphylaxis in mice. journal of allergy and clinical immunology Reber, L. L., Marichal, T., Mukai, K., Kita, Y., Tokuoka, S. M., Roers, A., Hartmann, K., Karasuyama, H., Nadeau, K. C., Tsai, M., Galli, S. J. 2013; 132 (4): 881-888 e11

    View details for DOI 10.1016/j.jaci.2013.06.008

    View details for PubMedID 23915716

  • In utero arsenic exposure and infant infection in a United States cohort: A prospective study ENVIRONMENTAL RESEARCH Farzan, S. F., Korrick, S., Li, Z., Enelow, R., Gandolfi, A. J., Madan, J., Nadeau, K., Karagas, M. R. 2013; 126: 24-30

    Abstract

    Arsenic (As), a ubiquitous environmental toxicant, has recently been linked to disrupted immune function and enhanced infection susceptibility in highly exposed populations. In drinking water, as levels above the EPA maximum contaminant level occur in our US study area and are a particular health concern for pregnant women and infants. As a part of the New Hampshire Birth Cohort Study, we investigated whether in utero exposure to As affects risk of infant infections. We prospectively obtained information on 4-month-old infants (n=214) using a parental telephone survey on infant infections and symptoms, including respiratory infections, diarrhea and specific illnesses, as well as the duration and severity of infections. Using logistic regression and Poisson models, we evaluated the association between maternal urinary As during pregnancy and infection risks adjusted for potentially confounding factors. Maternal urinary As concentrations were related to total number of infections requiring a physician visit (relative risk (RR) per one-fold increase in As in urine=1.5; 95% confidence interval (CI)=1.0, 2.1) or prescription medication (RR=1.6; 95% CI=1.1, 2.4), as well as lower respiratory infections treated with prescription medication (RR=3.3; 95% CI=1.2, 9.0). Associations were observed with respiratory symptoms (RR=4.0; 95% CI=1.0, 15.8), upper respiratory infections (RR=1.6; 95% CI=1.0, 2.5), and colds treated with prescription medication (RR=2.3; 95% CI=1.0, 5.2). Our results provide initial evidence that in utero As exposure may be related to infant infection and infection severity and provide insight into the early life impacts of fetal As exposure.

    View details for DOI 10.1016/j.envres.2013.05.001

    View details for Web of Science ID 000326135200004

    View details for PubMedID 23769261

  • Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Chen, R., Giliani, S., Lanzi, G., Mias, G. I., Lonardi, S., Dobbs, K., Manis, J., Im, H., Gallagher, J. E., Phanstiel, D. H., Euskirchen, G., Lacroute, P., Bettinger, K., Moratto, D., Weinacht, K., Montin, D., Gallo, E., Mangili, G., Porta, F., Notarangelo, L. D., Pedretti, S., Al-Herz, W., Alfahdli, W., Comeau, A. M., Traister, R. S., Pai, S., Carella, G., Facchetti, F., Nadeau, K. C., Snyder, M., Notarangelo, L. D. 2013; 132 (3): 656-?

    View details for DOI 10.1016/j.jaci.2013.06.013

    View details for Web of Science ID 000323612000018

    View details for PubMedID 23830146

  • Food allergy diagnosis and therapy: where are we now? IMMUNOTHERAPY Syed, A., Kohli, A., Nadeau, K. C. 2013; 5 (9): 931-944

    Abstract

    Food allergy is a growing worldwide epidemic that adversely effects up to 10% of the population. Causes and risk factors remain unclear and diagnostic methods are imprecise. There is currently no accepted treatment for food allergy. Therefore, there is an imminent need for greater understanding of food allergies, revised diagnostics and development of safe, effective therapies. Oral immunotherapy provides a particularly promising avenue, but is still highly experimental and not ready for clinical use.

    View details for DOI 10.2217/imt.13.93

    View details for Web of Science ID 000323735600007

    View details for PubMedID 23998729

  • Differentiating the roles of STAT5B and STAT5A in human CD4(+) T cells CLINICAL IMMUNOLOGY Jenks, J. A., Seki, S., Kanai, T., Huang, J., Morgan, A. A., Scalco, R. C., Nath, R., Bucayu, R., Wit, J. M., Al-Herz, W., Ramadan, D., Jorge, A. A., Bacchetta, R., Hwa, V., Rosenfeld, R., Nadeau, K. C. 2013; 148 (2): 227-236

    Abstract

    STAT5A and STAT5B are highly homologous proteins whose distinctive roles in human immunity remain unclear. However, STAT5A sufficiency cannot compensate for STAT5B defects, and human STAT5B deficiency, a rare autosomal recessive primary immunodeficiency, is characterized by chronic lung disease, growth failure and autoimmunity associated with regulatory T cell (Treg) reduction. We therefore hypothesized that STAT5A and STAT5B play unique roles in CD4(+) T cells. Upon knocking down STAT5A or STAT5B in human primary T cells, we found differentially regulated expression of FOXP3 and IL-2R in STAT5B knockdown T cells and down-regulated Bcl-X only in STAT5A knockdown T cells. Functional ex vivo studies in homozygous STAT5B-deficient patients showed reduced FOXP3 expression with impaired regulatory function of STAT5B-null Treg cells, also of increased memory phenotype. These results indicate that STAT5B and STAT5A act partly as non-redundant transcription factors and that STAT5B is more critical for Treg maintenance and function in humans.

    View details for DOI 10.1016/j.clim.2013.04.014

    View details for Web of Science ID 000322101300009

    View details for PubMedID 23773921

    View details for PubMedCentralID PMC4169138

  • DASH for asthma: A pilot study of the DASH diet in not-well-controlled adult asthma CONTEMPORARY CLINICAL TRIALS Ma, J., Strub, P., Lavori, P. W., Buist, S., Camargo, C. A., Nadeau, K. C., Wilson, S. R., Xiao, L. 2013; 35 (2): 55-67

    Abstract

    This pilot study aims to provide effect size confidence intervals, clinical trial and intervention feasibility data, and procedural materials for a full-scale randomized controlled trial that will determine the efficacy of Dietary Approaches to Stop Hypertension (DASH) as adjunct therapy to standard care for adults with uncontrolled asthma. The DASH diet encompasses foods (e.g., fresh fruit, vegetables, and nuts) and antioxidant nutrients (e.g., vitamins A, C, E, and zinc) with potential benefits for persons with asthma, but it is unknown whether the whole diet is beneficial. Participants (n=90) will be randomized to receive usual care alone or combined with a DASH intervention consisting of 8 group and 3 individual sessions during the first 3months, followed by at least monthly phone consultations for another 3months. Follow-up assessments will occur at 3 and 6months. The primary outcome measure is the 7-item Juniper Asthma Control Questionnaire, a validated composite measure of daytime and nocturnal symptoms, activity limitations, rescue medication use, and percentage predicted forced expiratory volume in 1second. We will explore changes in inflammatory markers important to asthma pathophysiology (e.g., fractional exhaled nitric oxide) and their potential to mediate the intervention effect on disease control. We will also conduct pre-specified subgroup analyses by genotype (e.g., polymorphisms on the glutathione S transferase gene) and phenotype (e.g., atopy, obesity). By evaluating a dietary pattern approach to improving asthma control, this study could advance the evidence base for refining clinical guidelines and public health recommendations regarding the role of dietary modifications in asthma management.

    View details for DOI 10.1016/j.cct.2013.04.008

    View details for Web of Science ID 000322560900007

    View details for PubMedID 23648395

  • The Use of Epinephrine in Acute Allergic Reaction to Food PEDIATRIC ANNALS Dominguez, T. L., Begin, P., Nadeau, K. C. 2013; 42 (7): 293-295

    View details for DOI 10.3928/00904481-20130619-14

    View details for Web of Science ID 000322203700019

    View details for PubMedID 23805971

  • The Impact of Food Allergies on Quality of Life PEDIATRIC ANNALS Bacal, L. R., Nadeau, K. C. 2013; 42 (7): 141-145
  • Diagnosis of Food Allergy PEDIATRIC ANNALS Begin, P., Nadeau, K. C. 2013; 42 (6): 102-109

    Abstract

    Diagnosis of food allergy can be challenging. Given the limited specificity of available allergy tests, these need to be interpreted in light of pre-test probability that is determined by a careful history. Using likelihood ratios calculated from previous publication may allow a more individualized assessment. This approach is likely to be most useful in patients with low to moderate results, below the 95% positive predictive value for that food. This review covers the diagnostic approach of immunoglobulin E-mediated food allergy. We first focus on the pre-test clinical assessment of a patient with a suspected food allergy. We then compare currently available diagnostic tests and discuss their performance for frequent food allergens. Finally, we conclude with the interpretation of allergy tests in light of the pre-test assessment to determine final probability of food allergy and indications for referral to an allergy specialist for food challenge.

    View details for DOI 10.3928/00904481-20130522-10

    View details for Web of Science ID 000322201500003

    View details for PubMedID 23718238

  • Use of a Novel Protocol to Successfully Characterize and Treat Immune-Mediated Acute Hepatitis and Liver Failure in Children 13th American Transplant Congress (ATC) McKenzie, R., Berquist, W., Nadeau, K., Chen, S., Sibley, R., Cox, K. WILEY-BLACKWELL. 2013: 49–49
  • Markers of Antigen Presentation and Activation on Eosinophils and T Cells in the Esophageal Tissue of Patients With Eosinophilic Esophagitis JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Le-Carlson, M., Seki, S., Abarbanel, D., Quiros, A., Cox, K., Nadeau, K. C. 2013; 56 (3): 257-262

    Abstract

    Evidence suggests eosinophils may be acting as antigen-presenting cells (APCs) by presenting antigen to T cells. We investigated the surface proteins of eosinophils and T cells in the esophageal biopsies of patients with eosinophilic esophagitis (EoE), patients with gastroesophageal reflux disease (GERD), and healthy controls (HCs).: Subjects were categorized as EoE, GERD, or HC. In esophageal tissue, EG2+ eosinophils were stained for the APC markers, CD40 or CD80, via immunohistochemistry. CD3+ T cells were stained for costimulatory markers, CD40L or CD28, and for activation markers, CD69 or CD134, via immunofluorescence or immunohistochemistry.Eosinophils stained with CD40 and CD80. The number of EG2+CD40+ cells was increased in EoE (mean 19.1±14.8 cells/high-power field [HPF], n=11), compared with GERD (mean 0.13±0.19 cells/HPF, n=5, P<0.01) and HC (mean 0.3±0.7 cells/HPF, n=5, P<0.01). There was an elevation in EG2+CD80+ cells in EoE (mean 18.1±16.2 cells/HPF, n=10), GERD (mean 1.7±2.8 cells/HPF, n=6, P<0.01), or HC (mean 0.8±1.3 cells/HPF, n=6, P<0.01). CD3+ T cells stained with CD40L (not quantified). CD3+ T cells stained with CD28 at elevated levels in EoE (mean 14±8.7 cells/HPF, n=9) versus GERD (mean 3.3±1.2 cells/HPF, n=6, P<0.05) or HC (mean 3.0±3.2 cells/HPF, n=7, P<0.01). The number of CD3+CD69+ cells was highest in EoE (mean 14.8±7.5 cells/HPF, n=6) versus GERD (mean 0.8±0.9 cells/HPF, n=6, P<0.001) or HC (mean 2.7±2.5 cells/HPF, n=6, P<0.001).We show that esophageal eosinophils express CD40 and CD80, and T cells with CD40L, CD28, and CD69. The number of double-stained cells was higher in EoE in comparison to control groups. These data support the hypothesis that eosinophils in EoE may act as APCs, activating T cells.

    View details for DOI 10.1097/MPG.0b013e3182758d49

    View details for Web of Science ID 000315461400010

    View details for PubMedID 23059644

  • Immunomodulatory effect of vancomycin on Treg in pediatric inflammatory bowel disease and primary sclerosing cholangitis. Journal of clinical immunology Abarbanel, D. N., Seki, S. M., Davies, Y., Marlen, N., Benavides, J. A., Cox, K., Nadeau, K. C., Cox, K. L. 2013; 33 (2): 397-406

    Abstract

    Vancomycin has been shown to affect tumor necrosis factor-alpha (TNF-α) pathways as an immunomodulator; this is thought to be separate from its function as an antibiotic [1]. Previous studies have shown that oral vancomycin (OV) is an effective treatment for concomitant primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) in children [2, 3]. Since both diseases are associated with immune dysfunction, we hypothesized that vancomycin's therapeutic effect in IBD and PSC occurs through immunomodulation. Therefore, we examined the in vivo immunological changes that occur during OV treatment of 14 children with PSC and IBD. Within 3 months of OV administration, peripheral gamma-glutamyl transpeptidase (GGT) and alanine aminotransferase (ALT) concentrations, white blood cell (WBC) counts, and neutrophil counts normalized from elevated levels before treatment. Patients also demonstrated improved biliary imaging studies, liver biopsies and IBD symptoms and biopsies. Additionally, plasma transforming growth factor beta (TGF-β) levels were increased without concurrent shifts in Th1-or Th2-associated cytokine production. Peripheral levels of CD4 + CD25hiCD127lo and CD4 + FoxP3+ regulatory T (Treg) cells also increased in OV-treated PSC + IBD patients compared to pretreatment levels. A unique case study shows that the therapeutic effects of OV in the treatment of PSC + IBD do not always endure after OV discontinuation, with relapse of PSC associated with a decrease in blood Treg levels; subsequent OV retreatment was then associated with a rise in blood Treg levels and normalization of liver function tests (LFTs). Taken together, these studies support immune-related pathophysiology of PSC with IBD, which is responsive to OV.

    View details for DOI 10.1007/s10875-012-9801-1

    View details for PubMedID 23054338

  • Molecular Mechanisms Involved in Dendritic Cell-Dependent Regulatory T Cell Generation During Immunotherapy Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI) Garcia, M. A., Nadeau, K. MOSBY-ELSEVIER. 2013: AB127–AB127
  • Multi-Allergen Oral Immunotherapy Improves Quality of Life in Subjects with Food Allergies Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI) Otani, I., Dominguez, T. L., Sciancalepore, A., Mehrotra, A., Pineda, D., Nadeau, K. MOSBY-ELSEVIER. 2013: AB58–AB58
  • Efficacy of Oral Immunotherapy and Anti-IgE Antibody-Adjunctive Treatment in Patients with Multiple Food Allergies Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI) Dominguez, T. L., Wilson, S. P., Sciancalepore, A., Pineda, D., Mehrotra, A., Rubinstein, S. W., Goldsobel, A. B., Mulligan, M. J., Bocian, R. C., Cummings, N., Nadeau, K. MOSBY-ELSEVIER. 2013: AB93–AB93
  • Epigenetically mediated pathogenic effects of phenanthrene on regulatory T cells. Journal of toxicology Liu, J., Zhang, L., Winterroth, L. C., Garcia, M., Weiman, S., Wong, J. W., Sunwoo, J. B., Nadeau, K. C. 2013; 2013: 967029-?

    Abstract

    Phenanthrene (Phe), a polycyclic aromatic hydrocarbon (PAH), is a major constituent of urban air pollution. There have been conflicting results regarding the role of other AhR ligands 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) and 6-formylindolo [3,2-b]carbazole (FICZ) in modifying regulatory T cell populations (Treg) or T helper (Th)17 differentiation, and the effects of Phe have been understudied. We hypothesized that different chemical entities of PAH induce Treg to become either Th2 or Th17 effector T cells through epigenetic modification of FOXP3. To determine specific effects on T cell populations by phenanthrene, primary human Treg were treated with Phe, TCDD, or FICZ and assessed for function, gene expression, and phenotype. Methylation of CpG sites within the FOXP3 locus reduced FOXP3 expression, leading to impaired Treg function and conversion of Treg into a CD4(+)CD25(lo) Th2 phenotype in Phe-treated cells. Conversely, TCDD treatment led to epigenetic modification of IL-17A and conversion of Treg to Th17 T cells. These findings present a mechanism by which exposure to AhR-ligands mediates human T cell responses and begins to elucidate the relationship between environmental exposures, immune modulation, and initiation of human disease.

    View details for DOI 10.1155/2013/967029

    View details for PubMedID 23533402

    View details for PubMedCentralID PMC3606805

  • Immunologic Effects of Omalizumab in Children with Severe Refractory Atopic Dermatitis: A Randomized, Placebo-Controlled Clinical Trial INTERNATIONAL ARCHIVES OF ALLERGY AND IMMUNOLOGY Iyengar, S. R., Hoyte, E. G., Loza, A., Bonaccorso, S., Chiang, D., Umetsu, D. T., Nadeau, K. C. 2013; 162 (1): 89-93

    Abstract

    Background: Severe refractory atopic dermatitis (AD) is a chronic, debilitating condition that is associated with elevated serum immunoglobulin E (IgE) levels. Thymic stromal lymphopoietin (TSLP), thymus and activation-regulated chemokine (TARC) and OX40 ligand (OX40L) are important immunologic factors involved in the pathogenesis of AD. Omalizumab, an anti-IgE antibody indicated for use in allergic asthma, is implicated in regulating allergen presentation by dendritic cells and the T cell response during the effector phases of allergic disease. We investigated if anti-IgE therapy modulates the allergen-specific responses mediated by the TSLP pathway in young patients with severe refractory AD. Methods: This was a randomized, double-blind, placebo-controlled study of 8 patients between the ages of 4 and 22 years (mean = 11.6 years) with severe refractory AD (clinical trials.gov NCT01678092). Serum IgE ranged from 218 to 1,890 (mean = 1,068 IU/ml). Subjects received omalizumab (n = 4) or placebo (n = 4) every 2-4 weeks over 24 weeks using a regimen extrapolated from the package insert. TSLP, TARC, OX40L and other cytokines involved in AD were measured by using cytometric bead arrays. Results: All patients receiving omalizumab had strikingly decreased levels of TSLP, OX40L, TARC (involved in Th2 polarization) and interleukin (IL)-9 compared to placebo. In addition, there was a marked increase in IL-10, a tolerogenic cytokine, in the omalizumab-treated group. Patients on anti-IgE therapy had an improvement in clinical outcomes as measured by the SCORAD system; however, these effects were comparable to improvements in the control group. Conclusions: Anti-IgE therapy with omalizumab decreases levels of cytokines that are involved in Th2 polarization and allergic inflammation, including TSLP, TARC and OX40L.

    View details for DOI 10.1159/000350486

    View details for Web of Science ID 000322776600013

    View details for PubMedID 23816920

  • Asthma Discordance in Twins Is Linked to Epigenetic Modifications of T Cells PLOS ONE Runyon, R. S., Cachola, L. M., Rajeshuni, N., Hunter, T., Garcia, M., Ahn, R., Lurmann, F., Krasnow, R., Jack, L. M., Miller, R. L., Swan, G. E., Kohli, A., Jacobson, A. C., Nadeau, K. C. 2012; 7 (11)

    Abstract

    T cells mediate the inflammatory responses observed in asthma among genetically susceptible individuals and have been suspected to be prone to epigenetic regulation. However, these relationships are not well established from past clinical studies that have had limited capacity to control for the effects of variable genetic predisposition and early environmental exposures. Relying on a cohort of monozygotic twins discordant for asthma we sought to determine if epigenetic modifications in T cells were associated with current asthma and explored whether such modifications were associated with second hand smoke exposures. Our study was conducted in a monozygotic twin cohort of adult twin pairs (n = 21) all discordant for asthma. Regulatory T cell (Treg) and effector T cell (Teff) subsets were assessed for levels of cellular function, protein expression, gene expression and CpG methylation within Forkhead box P3 (FOXP3) and interferon gamma-γ (IFNγ) loci. Comparisons by asthma and current report of exposure to second hand smoke were made. Treg from asthmatic discordant twins demonstrated decreased FOXP3 protein expression and impaired Treg function that was associated with increased levels of CpG methylation within the FOXP3 locus when compared to their non-asthmatic twin partner. In parallel, Teff from discordant asthmatic twins demonstrated increased methylation of the IFNγ locus, decreased IFNγ expression and reduced Teff function when compared to Teff from the non-asthmatic twin. Finally, report of current exposure to second hand smoke was associated with modifications in both Treg and Teff at the transcriptional level among asthmatics. The results of the current study provide evidence for differential function of T cell subsets in monozygotic twins discordant for asthma that are regulated by changes in DNA methylation. Our preliminary data suggest exposure to second hand smoke may augment the modified T cell responses associated with asthma.

    View details for DOI 10.1371/journal.pone.0048796

    View details for Web of Science ID 000312376100014

    View details for PubMedID 23226205

    View details for PubMedCentralID PMC3511472

  • CHARACTERIZATION OF AUTOANTIBODY PROFILE AMONG PATIENTS WITH PRIMARY IMMUNODEFICIENCY SECONDARY TO RAG MUTATIONS 15th Biennial Meeting of the European-Society-for-Immunodeficiency (ESID) Walter, J. E., Matthew, D., Lee, Y. N., Recher, M., Patrizi, L., Al-Herz, W., Cowan, M., Puck, J., Bleesing, J., Filipovich, L., Niehues, T., Schuetz, C., DRUCKER, G., Malech, H., De Ravin, S. S., Uzel, G., Facchetti, F., Gennery, A., Alenezi, H. M., Chinen, J., Dbaibo, G., El Ghazali, G., Pasic, S., Chen, K., Nadeau, K., Abraham, R., Giliani, S., Balboni, M., Browne, S., Notarangelo, L. D. SPRINGER/PLENUM PUBLISHERS. 2012: 44–44
  • Epigenetic modifications and improved regulatory T-cell function in subjects undergoing dual sublingual immunotherapy JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Swamy, R. S., Reshamwala, N., Hunter, T., Vissamsetti, S., Santos, C. B., Baroody, F. M., Hwang, P. H., Hoyte, E. G., Garcia, M. A., Nadeau, K. C. 2012; 130 (1): 215-?

    Abstract

    Allergen-specific immunotherapy is the only mode of therapy that has been demonstrated to offer a cure in patients with IgE-mediated respiratory allergies.We sought to demonstrate the safety and efficacy of timothy grass (TG) and dust mite (DM) dual sublingual immunotherapy (SLIT) and to begin to investigate the immune mechanisms involved in successful immunotherapy with multiple allergens.The safety and efficacy of dual SLIT with TG and DM in children and adults with demonstrated allergies to TG and DM were investigated in a single-center, randomized, double-blind, controlled phase I study. Thirty subjects received either TG and DM dual SLIT (n= 20) or placebo (n = 10). Immune parameters were evaluated for differentiation of desensitized subjects from control subjects.Subjects treated with dual SLIT had decreased rhinoconjunctivitis scores (P < .001) and medication use scores (P < .001) and reduced responses to TG and DM allergen based on results of skin prick tests or nasal disk challenges (P < .01 and P < .001, respectively) compared with placebo-treated control subjects. An increase in TG- and DM-specific IgG(4) levels, reduced allergen-specific IgE levels, and subsequent basophil activation were observed in the active treatment group. Dual SLIT promoted allergen-specific suppressive CD4(+)CD25(high)CD127(low)CD45RO(+) forkhead box protein 3 (Foxp3)(+) memory regulatory T cells with reduced DNA methylation of CpG sites within the Foxp3 locus.The results of this pilot study suggest that dual SLIT could be an effective means to treat subjects with sensitivities to a variety of allergens and that long-term tolerance might be induced by epigenetic modifications of Foxp3 in memory regulatory T cells.

    View details for DOI 10.1016/j.jaci.2012.04.021

    View details for Web of Science ID 000306644800030

    View details for PubMedID 22677046

    View details for PubMedCentralID PMC4161455

  • Modulation of mTOR Effector Phosphoproteins in Blood Basophils from Allergic Patients JOURNAL OF CLINICAL IMMUNOLOGY Gernez, Y., Tirouvanziam, R., Reshamwala, N., Yu, G., Weldon, B. C., Galli, S. J., Herzenberg, L. A., Nadeau, K. C. 2012; 32 (3): 565-573

    Abstract

    The mammalian target of rapamycin (mTOR) pathway contributes to various immunoinflammatory processes. Yet, its potential involvement in basophil responses in allergy remains unclear. In this pilot study, we quantified two key mTOR effector phosphoproteins, the eukaryotic initiation factor 4E (peIF4E) and S6 ribosomal protein (pS6rp), in blood basophils from nut allergy patients (NA, N = 16) and healthy controls (HC, N = 13). Without stimulation in vitro, basophil peIF4E levels were higher in NA than HC subjects (P = 0.014). Stimulation with nut (offending) but not chicken / rice (non-offending) extract increased basophil peIF4E and pS6rp levels (+32%, P = 0.018, and +98%, P = 0.0026, respectively) in NA but not HC subjects, concomitant with increased surface levels of CD203c and CD63, both known to reflect basophil activation. Pre-treatment with the mTOR inhibitor rapamycin decreased pS6rp and CD203c responses in nut extract-stimulated basophils in NA subjects. Thus, basophil responses to offending allergens are associated with modulation of mTOR effector phosphoproteins.

    View details for DOI 10.1007/s10875-012-9651-x

    View details for Web of Science ID 000305982100019

    View details for PubMedID 22350221

  • Changes in antigen-specific T-cell number and function during oral desensitization in cow's milk allergy enabled with omalizumab MUCOSAL IMMUNOLOGY Bedoret, D., Singh, A. K., Shaw, V., Hoyte, E. G., HAMILTON, R., DeKruyff, R. H., Schneider, L. C., Nadeau, K. C., Umetsu, D. T. 2012; 5 (3): 267-276

    Abstract

    Food allergy is a major public health problem, for which there is no effective treatment. We examined the immunological changes that occurred in a group of children with significant cow's milk allergy undergoing a novel and rapid high-dose oral desensitization protocol enabled by treatment with omalizumab (anti-immunoglobulin (Ig)E monoclonal antibodies). Within a week of treatment, the CD4(+) T-cell response to milk was nearly eliminated, suggesting anergy in, or deletion of, milk-specific CD4(+) T cells. Over the following 3 months while the subjects remained on high doses of daily oral milk, the CD4(+) T-cell response returned, characterized by a shift from interleukin-4 to interferon-γ production. Desensitization was also associated with reduction in milk-specific IgE and a 15-fold increase in milk-specific IgG4. These studies suggest that high-dose oral allergen desensitization may be associated with deletion of allergen-specific T cells, without the apparent development of allergen-specific Foxp3(+) regulatory T cells.

    View details for DOI 10.1038/mi.2012.5

    View details for Web of Science ID 000303011300006

    View details for PubMedID 22318492

  • B cell-intrinsic deficiency of the Wiskott-Aldrich syndrome protein (WASp) causes severe abnormalities of the peripheral B-cell compartment in mice BLOOD Recher, M., Burns, S. O., de la Fuente, M. A., Volpi, S., Dahlberg, C., Walter, J. E., Moffitt, K., Mathew, D., Honke, N., Lang, P. A., Patrizi, L., Falet, H., Keszei, M., Mizui, M., Csizmadia, E., Candotti, F., Nadeau, K., Bouma, G., Delmonte, O. M., Frugoni, F., Fomin, A. B., Buchbinder, D., Lundequist, E. M., Massaad, M. J., Tsokos, G. C., Hartwig, J., Manis, J., Terhorst, C., Geha, R. S., Snapper, S., Lang, K. S., Malley, R., Westerberg, L., Thrasher, A. J., Notarangelo, L. D. 2012; 119 (12): 2819-2828

    Abstract

    Wiskott Aldrich syndrome (WAS) is caused by mutations in the WAS gene that encodes for a protein (WASp) involved in cytoskeleton organization in hematopoietic cells. Several distinctive abnormalities of T, B, and natural killer lymphocytes; dendritic cells; and phagocytes have been found in WASp-deficient patients and mice; however, the in vivo consequence of WASp deficiency within individual blood cell lineages has not been definitively evaluated. By conditional gene deletion we have generated mice with selective deficiency of WASp in the B-cell lineage (B/WcKO mice). We show that this is sufficient to cause a severe reduction of marginal zone B cells and inability to respond to type II T-independent Ags, thereby recapitulating phenotypic features of complete WASp deficiency. In addition, B/WcKO mice showed prominent signs of B-cell dysregulation, as indicated by an increase in serum IgM levels, expansion of germinal center B cells and plasma cells, and elevated autoantibody production. These findings are accompanied by hyperproliferation of WASp-deficient follicular and germinal center B cells in heterozygous B/WcKO mice in vivo and excessive differentiation of WASp-deficient B cells into class-switched plasmablasts in vitro, suggesting that WASp-dependent B cell-intrinsic mechanisms critically contribute to WAS-associated autoimmunity.

    View details for DOI 10.1182/blood-2011-09-379412

    View details for Web of Science ID 000302121700019

    View details for PubMedID 22302739

  • Personal Omics Profiling Reveals Dynamic Molecular and Medical Phenotypes CELL Chen, R., Mias, G. I., Li-Pook-Than, J., Jiang, L., Lam, H. Y., Chen, R., Miriami, E., Karczewski, K. J., Hariharan, M., Dewey, F. E., Cheng, Y., Clark, M. J., Im, H., Habegger, L., Balasubramanian, S., O'Huallachain, M., Dudley, J. T., Hillenmeyer, S., Haraksingh, R., Sharon, D., Euskirchen, G., Lacroute, P., Bettinger, K., Boyle, A. P., Kasowski, M., Grubert, F., Seki, S., Garcia, M., Whirl-Carrillo, M., Gallardo, M., Blasco, M. A., Greenberg, P. L., Snyder, P., Klein, T. E., Altman, R. B., Butte, A. J., Ashley, E. A., Gerstein, M., Nadeau, K. C., Tang, H., Snyder, M. 2012; 148 (6): 1293-1307

    Abstract

    Personalized medicine is expected to benefit from combining genomic information with regular monitoring of physiological states by multiple high-throughput methods. Here, we present an integrative personal omics profile (iPOP), an analysis that combines genomic, transcriptomic, proteomic, metabolomic, and autoantibody profiles from a single individual over a 14 month period. Our iPOP analysis revealed various medical risks, including type 2 diabetes. It also uncovered extensive, dynamic changes in diverse molecular components and biological pathways across healthy and diseased conditions. Extremely high-coverage genomic and transcriptomic data, which provide the basis of our iPOP, revealed extensive heteroallelic changes during healthy and diseased states and an unexpected RNA editing mechanism. This study demonstrates that longitudinal iPOP can be used to interpret healthy and diseased states by connecting genomic information with additional dynamic omics activity.

    View details for DOI 10.1016/j.cell.2012.02.009

    View details for Web of Science ID 000301889500023

    View details for PubMedID 22424236

    View details for PubMedCentralID PMC3341616

  • Multiplex meta-analysis of RNA expression to identify genes with variants associated with immune dysfunction JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION Morgan, A. A., Pyrgos, V. J., Nadeau, K. C., Williamson, P. R., Butte, A. J. 2012; 19 (2): 284-288

    Abstract

    We demonstrate a genome-wide method for the integration of many studies of gene expression of phenotypically similar disease processes, a method of multiplex meta-analysis. We use immune dysfunction as an example disease process.We use a heterogeneous collection of datasets across human and mice samples from a range of tissues and different forms of immunodeficiency. We developed a method integrating Tibshirani's modified t-test (SAM) is used to interrogate differential expression within a study and Fisher's method for omnibus meta-analysis to identify differentially expressed genes across studies. The ability of this overall gene expression profile to prioritize disease associated genes is evaluated by comparing against the results of a recent genome wide association study for common variable immunodeficiency (CVID).Our approach is able to prioritize genes associated with immunodeficiency in general (area under the ROC curve = 0.713) and CVID in particular (area under the ROC curve = 0.643).This approach may be used to investigate a larger range of failures of the immune system. Our method may be extended to other disease processes, using RNA levels to prioritize genes likely to contain disease associated DNA variants.

    View details for DOI 10.1136/amiajnl-2011-000657

    View details for Web of Science ID 000300768100023

    View details for PubMedID 22319178

    View details for PubMedCentralID PMC3277634

  • Autoimmune regulator (AIRE) contributes to Dectin-1-induced TNF-alpha production and complexes with caspase recruitment domain-containing protein 9 (CARD9), spleen tyrosine kinase (Syk), and Dectin-1 JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Pedroza, L. A., Kumar, V., Sanborn, K. B., Mace, E. M., Niinikoski, H., Nadeau, K., Vasconcelos, D. d., Perez, E., Jyonouchi, S., Jyonouchi, H., Banerjee, P. P., Ruuskanen, O., Condino-Neto, A., Orange, J. S. 2012; 129 (2): 464-U287

    Abstract

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome is a complex immunologic disease caused by mutation of the autoimmune regulator (AIRE) gene. Autoimmunity in patients with APECED syndrome has been shown to result from deficiency of AIRE function in transcriptional regulation of thymic peripheral tissue antigens, which leads to defective T-cell negative selection. Candidal susceptibility in patients with APECED syndrome is thought to result from aberrant adaptive immunity.To determine whether AIRE could function in anticandidal innate immune signaling, we investigated an extrathymic role for AIRE in the immune recognition of β-glucan through the Dectin-1 pathway, which is required for defense against Candida species.Innate immune signaling through the Dectin-1 pathway was assessed in both PBMCs from patients with APECED syndrome and a monocytic cell line. Subcellular localization of AIRE was assessed by using confocal microscopy.PBMCs from patients with APECED syndrome had reduced TNF-α responses after Dectin-1 ligation but in part used a Raf-1-mediated pathway to preserve function. In the THP-1 human monocytic cell line, reducing AIRE expression resulted in significantly decreased TNF-α release after Dectin-1 ligation. AIRE formed a transient complex with the known Dectin-1 pathway components phosphorylated spleen tyrosine kinase and caspase recruitment domain-containing protein 9 after receptor ligation and localized with Dectin-1 at the cell membrane.AIRE can participate in the Dectin-1 signaling pathway, indicating a novel extrathymic role for AIRE and a defect that likely contributes to fungal susceptibility in patients with APECED syndrome.

    View details for DOI 10.1016/j.jaci.2011.08.027

    View details for Web of Science ID 000299951700026

    View details for PubMedID 21962774

  • Oral Immunotherapy and Anti-IgE Antibody-Adjunctive Treatment for Food Allergy IMMUNOLOGY AND ALLERGY CLINICS OF NORTH AMERICA Nadeau, K. C., Kohli, A., Iyengar, S., DeKruyff, R. H., Umetsu, D. T. 2012; 32 (1): 111-?

    Abstract

    One of the most promising therapies for food allergy is oral immunotherapy (OIT), in which small amounts of allergen are administered in increasing amounts, with the immediate goal of desensitization and the long-term goal of tolerance. However, safety and standardization concerns prevent its widespread use, and a subgroup of patients may experience severe allergic reactions. These concerns might be addressed by another promising therapy involving anti-IgE monoclonal antibodies (mAb), which can reduce allergic reactions associated with food administration. A recent pilot study combining anti-IgE mAb with OIT suggests that anti-IgE mAb might improve the safety, rapidity, and efficacy of OIT.

    View details for DOI 10.1016/j.iac.2011.11.004

    View details for Web of Science ID 000300467200010

    View details for PubMedID 22244236

  • The STAT5b Pathway Defect and Autoimmunity. Frontiers in immunology Kanai, T., Jenks, J., Nadeau, K. C. 2012; 3: 234-?

    Abstract

    The signal transducer and activator of transcription (STAT) 5b is a universal transcription factor that plays key biological roles in allergic diseases, immunodeficiencies, autoimmunities, cancers, hematological diseases, growth disorders, and lung diseases. The identification of distinct pathological manifestations of STAT5b deficiency in humans has highlighted the critical role of the STAT5b pathway. Proper gene transcription at IL-2R α, FOXP3, Bcl-2, and growth hormone (GH) associated loci are thought to be associated with normal STAT5b transcriptional activity. These genes are thought to play important roles in allergy/autoimmunity, immunodeficiency, cancer/anemia, and growth, respectively. The STAT5A and STAT5B genes are collocated on 17q11. Although these two monomeric proteins exhibit peptide sequence similarities of >90%, it is known through observations of STAT5b deficient subjects that STAT5a and STAT5b are not fully redundant in humans. Patients with STAT5b deficiency have decreased numbers of regulatory CD4(+)CD25(high) T cell (Treg) despite their STAT5a levels being normal. Prior studies on STAT5b deficient subjects have revealed immunological aberrations associated with the following disease phenotype: modest lymphopenia and decreased populations of Treg, γ-δ T cells, and natural killer (NK) cells. Most subjects with STAT5b deficiency show severe eczema, and autoimmune disease (juvenile idiopathic arthritis, autoimmune thyroiditis, idiopathic thrombocytic purpura) which are thought to be associated with Treg dysfunction. We will review the likely pathophysiological mechanisms associated with STAT5b deficiency.

    View details for DOI 10.3389/fimmu.2012.00234

    View details for PubMedID 22912632

  • The STAT5b pathway defect and autoimmunity FRONTIERS IN IMMUNOLOGY Kanai, T., Jenks, J., Nadeau, K. C. 2012; 3
  • Secondhand smoke in combination with ambient air pollution exposure is associated with increasedx CpG methylation and decreased expression of IFN-gamma in T effector cells and Foxp3 in T regulatory cells in children CLINICAL EPIGENETICS Kohli, A., Garcia, M. A., Miller, R. L., Maher, C., Humblet, O., Hammond, S. K., Nadeau, K. 2012; 4
  • Secondhand smoke in combination with ambient air pollution exposure is associated with increasedx CpG methylation and decreased expression of IFN-? in T effector cells and Foxp3 in T regulatory cells in children. Clinical epigenetics Kohli, A., Garcia, M. A., Miller, R. L., Maher, C., Humblet, O., Hammond, S. K., Nadeau, K. 2012; 4 (1): 17-?

    Abstract

    Secondhand smoke (SHS) and ambient air pollution (AAP) exposures have been associated with increased prevalence and severity of asthma and DNA modifications of immune cells. In the current study, we examined the association between SHS and AAP with DNA methylation and expression of interferon-gamma (IFN-γ) and forkhead box protein 3 (Foxp3) in T cell populations.Subjects 7-18 years old were recruited from Fresno (high AAP; n = 62) and Stanford, CA (low AAP; n = 40) and divided into SHS-exposed (Fresno: n = 31, Stanford: n = 6) and non-SHS-exposed (nSHS; Fresno: n = 31, Stanford: n = 34) groups. T cells purified from peripheral blood were assessed for levels of DNA methylation and expression of IFN-γ (in effector T cells) or Foxp3 (in regulatory T cells).Analysis showed a significant increase in mean % CpG methylation of IFN-γ and Foxp3 associated with SHS exposure (IFN-γ: FSHS 62.10%, FnSHS 41.29%, p < 0.05; SSHS 46.67%, SnSHS 24.85%, p < 0.05; Foxp3: FSHS 74.60%, FnSHS 54.44%, p < 0.05; SSHS 62.40%, SnSHS 18.41%, p < 0.05) and a significant decrease in mean transcription levels of both genes (IFN-γ: FSHS 0.75, FnSHS 1.52, p < 0.05; SHS 2.25, nSHS 3.53, p < 0.05; Foxp3: FSHS 0.75, FnSHS 3.29, p < 0.05; SSHS 4.8, SnSHS 7.2, p < 0.05). AAP was also associated with hypermethylation (IFN-γ: FSHS vs. SSHS, p < 0.05; FnSHS vs. SnSHS, p < 0.05; Foxp3: FSHS vs. SSHS, p < 0.05; FnSHS vs. SnSHS, p < 0.05) and decreased transcription of both genes (IFN-γ: FSHS vs. SSHS, p < 0.05; FnSHS vs. SnSHS, p < 0.05; Foxp3: FSHS vs. SSHS, p < 0.05; FnSHS vs. SnSHS, p < 0.05). Average methylation between AAP- and SHS-only exposures was not significantly different (IFN-γ: p = 0.15; Foxp3: p = 0.27), nor was Foxp3 expression (p = 0.08); IFN-γ expression was significantly decreased in AAP-only subjects (p < 0.05).Exposures to SHS and AAP are associated with significant hypermethylation and decreased expression of IFN-γ in Teffs and Foxp3 in Tregs. Relative contributions of each exposure to DNA modification and asthma pathogenesis warrant further investigation.

    View details for DOI 10.1186/1868-7083-4-17

    View details for PubMedID 23009259

  • The Safety of Peanut Oral Immunotherapy in Peanut-Allergic Subjects in a Single-Center Trial INTERNATIONAL ARCHIVES OF ALLERGY AND IMMUNOLOGY Yu, G. P., Weldon, B., Neale-May, S., Nadeau, K. C. 2012; 159 (2): 179-182

    Abstract

    Peanut allergy is the leading cause of food-related anaphylaxis, and accidental exposures are common. Oral immunotherapy (OIT) has been posited as a potential treatment.Patients aged 3-65 years with peanut-specific IgE ≥7 kU/l and/or a positive skin prick test with a history of an allergic reaction to peanut were recruited to undergo an OIT protocol. All adverse reactions were recorded by research staff or patients in real time.Twenty-four patients received 6,662 doses. Symptoms were mostly mild (84%), and only 3 severe gastrointestinal reactions required the administration of epinephrine. Abdominal pain was the most common reaction, followed by oropharyngeal and lip pruritus. Respiratory symptoms were rare.In this trial of OIT in adults and children, most reactions were mild.

    View details for DOI 10.1159/000336391

    View details for Web of Science ID 000305801300011

    View details for PubMedID 22678151

  • Genotype, phenotype, and outcomes of nine patients with T-B plus NK plus SCID PEDIATRIC TRANSPLANTATION Yu, G. P., Nadeau, K. C., Berk, D. R., de Saint Basile, G., Lambert, N., Knapnougel, P., Roberts, J., Kavanau, K., Dunn, E., Stiehm, E. R., Lewis, D. B., Umetsu, D. T., Puck, J. M., Cowan, M. J. 2011; 15 (7): 733-741

    Abstract

    There are few reports of clinical presentation, genotype, and HCT outcomes for patients with T-B+NK+ SCID. Between 1981 and 2007, eight of 84 patients with SCID who received and/or were followed after HCT at UCSF had the T-B+NK+ phenotype. One additional patient with T-B+NK+ SCID was identified as the sibling of a patient treated at UCSF. Chart reviews were performed. Molecular analyses of IL7R, IL2RG, JAK3, and the genes encoding the CD3 T-cell receptor components δ (CD3D), ε (CD3E), and ζ (CD3Z) were carried out. IL7R mutations were documented in four patients and CD3D mutations in two others. Three patients had no defects found. Only two of nine patients had an HLA-matched related HCT donor. Both survived, and neither developed GVHD. Five of seven recipients of haploidentical grafts survived. Although the majority of reported cases of T-B+NK+ SCID are caused by defects in IL7R, CD3 complex defects were also found in this series and should be considered when evaluating patients with T-B+NK+ SCID. Additional genes, mutations in which account for T-B+NK+ SCID, remain to be found. Better approaches to early diagnosis and HCT treatment are needed for patients lacking an HLA-matched related donor.

    View details for DOI 10.1111/j.1399-3046.2011.01563.x

    View details for Web of Science ID 000296049000020

    View details for PubMedID 21883749

    View details for PubMedCentralID PMC3196791

  • Monozygotic Twin Pair Showing Discordant Phenotype for X-linked Thrombocytopenia and Wiskott-Aldrich Syndrome: a Role for Epigenetics? JOURNAL OF CLINICAL IMMUNOLOGY Buchbinder, D., Nadeau, K., Nugent, D. 2011; 31 (5): 773-777

    Abstract

    Despite our increasing characterization of the molecular basis for many primary immunodeficiency states, significant heterogeneity in clinical and immunological phenotype exists. Epigenetic alterations have been implicated in the pathogenesis of immune dysregulation and may provide a unique paradigm to help us understand the phenotypic heterogeneity in primary immunodeficiency. The occurrence of X-linked thrombocytopenia (XLT) and Wiskott-Aldrich syndrome (WAS) in monozygotic twins is a rare occurrence which allows for the exploration of epigenetic alterations and associated phenotypic heterogeneity. We describe a pair of monozygotic twin brothers with a missense mutation in the WAS gene consistent with reduced expression of the WAS protein, a XLT phenotype, and a good prognosis. Despite this genotype and anticipated mild phenotype in both twins, a discordant phenotype has evolved in which one twin demonstrates asymptomatic thrombocytopenia and the other symptomatic thrombocytopenia, infectious complications, and autoimmunity. Characterization of the potential epigenetic contribution to the spectrum of XLT and WAS is described and the implications of these findings are discussed.

    View details for DOI 10.1007/s10875-011-9561-3

    View details for Web of Science ID 000296012300005

    View details for PubMedID 21710275

  • T(H)1, T(H)2, and T(H)17 cells instruct monocytes to differentiate into specialized dendritic cell subsets BLOOD Alonso, M. N., Wong, M. T., Zhang, A. L., Winer, D., Suhoski, M. M., Tolentino, L. L., Gaitan, J., Davidson, M. G., Kung, T. H., Galel, D. M., Nadeau, K. C., Kim, J., Utz, P. J., Soederstroem, K., Engleman, E. G. 2011; 118 (12): 3311-3320

    Abstract

    Monocytes and T helper (T(H)) cells rapidly infiltrate inflamed tissues where monocytes differentiate into inflammatory dendritic cells (DCs) through undefined mechanisms. Our studies indicate that T(H) cells frequently interact with monocytes in inflamed skin and elicit the differentiation of specialized DC subsets characteristic of these lesions. In psoriasis lesions, T(H)1 and T(H)17 cells interact with monocytes and instruct these cells to differentiate into T(H)1- and T(H)17-promoting DCs, respectively. Correspondingly, in acute atopic dermatitis, T(H)2 cells interact with monocytes and elicit the formation of T(H)2-promoting DCs. DC formation requires GM-CSF and cell contact, whereas T(H) subset specific cytokines dictate DC function and the expression of DC subset specific surface molecules. Moreover, the phenotypes of T cell-induced DC subsets are maintained after subsequent stimulation with a panel of TLR agonists, suggesting that T(H)-derived signals outweigh downstream TLR signals in their influence on DC function. These findings indicate that T(H) cells govern the formation and function of specialized DC subsets.

    View details for DOI 10.1182/blood-2011-03-341065

    View details for Web of Science ID 000295120900018

    View details for PubMedID 21813450

    View details for PubMedCentralID PMC3179399

  • Immunophenotyping of Peripheral Eosinophils Demonstrates Activation in Eosinophilic Esophagitis JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Tammie Nguyen, T., Gernez, Y., Fuentebella, J., Patel, A., Tirouvanziam, R., Reshamwala, N., Bass, D., Berquist, W. E., Cox, K. L., Kerner, J. A., Nadeau, K. C. 2011; 53 (1): 40-47

    Abstract

    Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder characterized by upper gastrointestinal symptoms and the presence of high numbers of eosinophils in the esophagus. Although eosinophils in the esophagus have been found to be activated in subjects with EoE, detailed studies of intracellular signaling pathways involved in the mechanism of activation of eosinophils in EoE have heretofore been limited. The aim of the study was to assess whether any surface molecules or transcription factors are activated in peripheral eosinophils in subjects with EoE.Eosinophils and CD3+ lymphocytes were identified directly from 50 μL of whole blood of EoE and control subjects. Using Hi-FACS, levels of surface activation markers, including CD66b, and intracellular phosphoepitopes, including phosphorylated forms of signal transducer and activator of transcription (phospho-STAT) 1 and 6, were measured within each cell subset.Levels of surface CD66b as well as levels of intracellular phospho-STAT1 and phospho-STAT6 in peripheral blood eosinophils were significantly higher for untreated subjects with EoE vs healthy controls (P < 0.05). Levels of phospho-STAT1 and phospho-STAT6 in peripheral blood eosinophils were lower in subjects with EoE on therapy versus untreated subjects with EoE (P < 0.05).Levels of phospho-STAT1 and phospho-STAT6, transcription factors involved in inflammatory processes, were both significantly higher in peripheral eosinophils from untreated (ie, newly diagnosed) subjects with EoE versus subjects with EoE on therapy, healthy controls. Blood-based measurements of CD66b and phospho-STAT levels in peripheral eosinophils may be beneficial for identifying EoE.

    View details for DOI 10.1097/MPG.0b013e318212647a

    View details for Web of Science ID 000291925500006

    View details for PubMedID 21694534

  • Rapid oral desensitization in combination with omalizumab therapy in patients with cow's milk allergy JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Nadeau, K. C., Schneider, L. C., Hoyte, L., Borras, I., Umetsu, D. T. 2011; 127 (6): 1622-1624

    View details for DOI 10.1016/j.jaci.2011.04.009

    View details for Web of Science ID 000291048500045

    View details for PubMedID 21546071

  • STAT5b Deficiency: An Unsuspected Cause of Growth Failure, Immunodeficiency, and Severe Pulmonary Disease JOURNAL OF PEDIATRICS Nadeau, K., Hwa, V., Rosenfeld, R. G. 2011; 158 (5): 701-708

    View details for DOI 10.1016/j.jpeds.2010.12.042

    View details for Web of Science ID 000289286100005

    View details for PubMedID 21414633

  • Serum amyloid A overrides T-reg anergy via monocyte-dependent and T-reg-intrinsic, SOCS3-associated pathways BLOOD Nguyen, K. D., Macaubas, C., Nadeau, K. C., Phi Truong, T., Yoon, T., Lee, T., Park, J. L., Mellins, E. D. 2011; 117 (14): 3793-3798

    Abstract

    The acute phase protein serum amyloid A (SAA) has been well characterized as an indicator of inflammation. Nevertheless, its functions in pro versus anti-inflammatory processes remain obscure. Here we provide unexpected evidences that SAA induces the proliferation of the tolerogenic subset of regulatory T cells (T(reg)). Intriguingly, SAA reverses T(reg) anergy via its interaction with monocytes to activate distinct mitogenic pathways in T(reg) but not effector T cells. This selective responsiveness of T(reg) correlates with their diminished expression of SOCS3 and is antagonized by T(reg)-specific induction of this regulator of cytokine signaling. Collectively, these evidences suggest a novel anti-inflammatory role of SAA in the induction of a micro-environment that supports T(reg) expansion at sites of infection or tissue injury, likely to curb (auto)-inflammatory responses.

    View details for DOI 10.1182/blood-2010-11-318832

    View details for Web of Science ID 000289265500014

    View details for PubMedID 21325601

    View details for PubMedCentralID PMC3296631

  • STAT5b deficiency: Lessons from STAT5b gene mutations BEST PRACTICE & RESEARCH CLINICAL ENDOCRINOLOGY & METABOLISM Hwa, V., Nadeau, K., Wit, J. M., Rosenfeld, R. G. 2011; 25 (1): 61-75

    Abstract

    Growth hormone (GH) regulates insulin-like growth factor (IGF)-I production primarily through activation of the GH receptor (GHR)-signal transducer and activator of transcription (STAT)-5b signaling cascade. One of four STAT proteins (STAT1, -3, -5a and -5b) activated by the GH-GHR system, the critical importance of STAT5b in IGF-I production became evident with the identification of homozygous, autosomal recessive STAT5b mutations in patients who presented with severe postnatal growth failure, growth hormone insensitivity syndrome (GHIS) and marked IGF-I deficiency. Unlike GHIS due to GHR mutations, patients carrying STAT5b mutations also presented with chronic pulmonary disease and evidence of perturbations of T-cell homeostasis. At present, no single treatment(s) is available to improve both poor statural growth and immune deficiency. Continued clinical evaluations of patients with STAT5b mutations and elucidating the impact of the mutation on STAT5b structure and function, are important to understanding the pathophysiology of this rare, complex, disease (MIM 245590).

    View details for DOI 10.1016/j.beem.2010.09.003

    View details for Web of Science ID 000289320500006

    View details for PubMedID 21396575

  • Pretreatment With Omalizumab Permits Rapid Oral Desensitization For Cow's Milk Allergy National Annual Scientific Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) Nadeau, K. C., Schneider, L. C., Hoyte, E., Borras, I., Umetsu, D. T. MOSBY-ELSEVIER. 2011: AB2–AB2
  • The Effect of Polycyclic Aromatic Hydrocarbons on Aryl Hydrocarbon Receptor and DNA Methyltransferase I Transcription National Annual Scientific Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) Cachola, L., Liu, J., McDonald-Hyman, C., Nadeau, K. MOSBY-ELSEVIER. 2011: AB127–AB127
  • Identification of CCR9+and CD103+Dendritic Cells in Tolerance Protocols for Food Allergy National Annual Scientific Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) Garcia, M. A., Yu, G., Singh, A. K., Longbottom, T., Nadeau, K. C. MOSBY-ELSEVIER. 2011: AB30–AB30
  • Use of Specific IgE and Skin Prick Test to Determine Clinical Reaction Severity. British journal of medicine and medical research Ta, V., Weldon, B., Yu, G., Humblet, O., Neale-May, S., Nadeau, K. 2011; 1 (4): 410-429

    Abstract

    AIMS: To determine whether specific IgE and skin prick test correlate better in predicting reaction severity during a double-blinded placebo controlled food challenge (DBPCFC) for egg, milk, and multiple tree nut allergens. STUDY DESIGN: Prospective study. PLACE AND DURATION OF STUDY: Department of Pediatrics, Stanford University School of Medicine, August 2009 and ongoing. METHODOLOGY: We examined the reaction severity of twenty-four subjects to nine possible food allergens: milk, egg, almond, cashew, hazelnut, peanut, sesame, pecan and walnut. Specific IgE and SPT were performed before each DBPCFC. DBPCFC results were classified into mild (1), moderate (2), or severe (3) reactions using a modified Bock's criteria. RESULTS: Twenty four subjects underwent a total of 80 DBPCFC. Eighty percent of all DBPCFCs resulted in a positive reaction. A majority, 71%, were classified as mild. No reactions occurred with a SPT of zero mm while three reactions occurred with a negative specific IgE. All reactions were reversible with medication. CONCLUSION: These data suggest that SPT and specific IgE levels are not associated with reaction severity (p<0.64 and 0.27, respectively). We also found that combining specific IgE and SPT improved specificity but did not help to achieve clinically useful sensitivity. For instance, an SPT > 5mm had a sensitivity of 91% and specificity of 50%. Combining SPT > 5mm and IgE > 7 resulted in a reduced sensitivity of 64%. Unexpectedly, a history of anaphylaxis 70% (n=17) was not predictive of anaphylaxis on challenge 4% (n=2).

    View details for PubMedID 22993721

  • STAT5b Deficiency: An Unsuspected Cause of Growth Failure, Immunodeficiency, and Severe Pulmonary Disease J Pediatr Nadeau KC, Hwa V, Rosenfeld R 2011; 158 (5): 701-8
  • Basophil CD203c Levels Are Increased at Baseline and Can Be Used to Monitor Omalizumab Treatment in Subjects with Nut Allergy INTERNATIONAL ARCHIVES OF ALLERGY AND IMMUNOLOGY Gernez, Y., Tirouvanziam, R., Yu, G., Ghosn, E. E., Reshamwala, N., Tammie Nguyen, T., Tsai, M., Galli, S. J., Herzenberg, L. A., Herzenberg, L. A., Nadeau, K. C. 2011; 154 (4): 318-327

    Abstract

    Basophils contribute to anaphylaxis and allergies. We examined the utility of assessing basophil-associated surface antigens (CD11b/CD63/CD123/CD203c/CD294) in characterizing and monitoring subjects with nut allergy.We used flow cytometry to analyze basophils at baseline (without any activation) and after ex vivo stimulation of whole blood by addition of nut or other allergens for 2, 10, and 30 min. We also evaluated whether basophil expression of CD11b/CD63/CD123/CD203c/CD294 was altered in subjects treated with anti-IgE monoclonal antibody (omalizumab) to reduce plasma levels of IgE.We demonstrate that basophil CD203c levels are increased at baseline in subjects with nut allergy compared to healthy controls (13 subjects in each group, p < 0.0001). Furthermore, we confirm that significantly increased expression of CD203c occurs on subject basophils when stimulated with the allergen to which the subject is sensitive and can be detected rapidly (10 min of stimulation, n = 11, p < 0.0008). In 5 subjects with severe peanut allergy, basophil CD203c expression following stimulation with peanut allergen was significantly decreased (p < 0.05) after 4 and 8 weeks of omalizumab treatment but returned toward pretreatment levels after treatment cessation.Subjects with nut allergy show an increase of basophil CD203c levels at baseline and following rapid ex vivo stimulation with nut allergen. Both can be reduced by omalizumab therapy. These results highlight the potential of using basophil CD203c levels for baseline diagnosis and therapeutic monitoring in subjects with nut allergy.

    View details for DOI 10.1159/000321824

    View details for Web of Science ID 000288529200007

    View details for PubMedID 20975283

    View details for PubMedCentralID PMC3214954

  • Migration of regulatory T cells toward airway epithelial cells is impaired in chronic rhinosinusitis with nasal polyposis CLINICAL IMMUNOLOGY Kim, Y. M., Munoz, A., Hwang, P. H., Nadeau, K. C. 2010; 137 (1): 111-121

    Abstract

    The pathogenesis of chronic rhinosinusitis with nasal polyposis (CRSwNP) is still unclear. To evaluate the role of regulatory T cells (Treg) in the pathogenesis of nasal polyposis, we tested migration potential of Treg purified from subjects with CRSwNP, CRS without NP and controls. The nasal tissue expressions of FOXP3 were analyzed by means of RT-PCR and double immunohistochemistry. Chemotaxis assays were used to evaluate the migration potential of Treg onto bronchial epithelial cells and primary nasal epithelial cells, and toward chemokines. FOXP3(+)CD3(+) cells frequency and FOXP3 transcript expression in nasal tissue, and migration potentials of Treg toward airway epithelial cells and CCL1 were significantly lower in CRSwNP compared with other groups (P<0.05). These results indicate that migration potential of Treg is decreased in CRSwNP subjects, and this may be one of the reasons why tissue infiltration of Treg was decreased as seen in the immunohistochemistry of nasal polyps from CRSwNP subjects.

    View details for DOI 10.1016/j.clim.2010.05.013

    View details for Web of Science ID 000282204900013

    View details for PubMedID 20598643

  • Ambient air pollution impairs regulatory T-cell function in asthma JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Nadeau, K., McDonald-Hyman, C., Noth, E. M., Pratt, B., Hammond, S. K., Balmes, J., Tager, I. 2010; 126 (4): 845-U280

    Abstract

    Asthma is the most frequent chronic disease in children, and children are at high risk for adverse health consequences associated with ambient air pollution (AAP) exposure. Regulatory T (Treg) cells are suppressors of immune responses involved in asthma pathogenesis. Treg-cell impairment is associated with increased DNA methylation of Forkhead box transcription factor 3 (Foxp3), a key transcription factor in Treg-cell activity. Because AAP exposure can induce epigenetic changes, we hypothesized that Treg-cell function would be impaired by AAP, allowing amplification of an inflammatory response.To assess whether exposure to AAP led to hypermethylation of the Foxp3 gene, causing impaired Treg-cell suppression and worsened asthma symptom scores.Children with and without asthma from Fresno, Calif (high pollution, Fresno Asthma Group [FA], n = 71, and Fresno Non Asthmatic Group, n = 30, respectively), and from Stanford, Calif (low pollution, Stanford Asthma Group, n = 40, and Stanford Non Asthmatic Group, n = 40), were enrolled in a cross-sectional study. Peripheral blood Treg cells were used in functional and epigenetic studies. Asthma outcomes were assessed by Global Initiative in Asthma score.Fresno Asthma Group Treg-cell suppression was impaired and FA Treg-cell chemotaxis were reduced compared with other groups (P ≤ .05). Treg-cell dysfunction was associated with more pronounced decreases in asthma Global Initiative in Asthma score in FA versus the Stanford Asthma Group. Foxp3 was decreased in FA compared with the Fresno Non Asthmatic Group (P ≤ .05). FA also contained significantly higher levels of methylation at the Foxp3 locus (P ≤ .05).Increased exposure to AAP is associated with hypermethylation of the Foxp3 locus, impairing Treg-cell function and increasing asthma morbidity. AAP could play a role in mediating epigenetic changes in Treg cells, which may worsen asthma by an immune mechanism.

    View details for DOI 10.1016/j.jaci.2010.08.008

    View details for Web of Science ID 000282510000024

    View details for PubMedID 20920773

  • Increased HLA-DR Expression on Tissue Eosinophils in Eosinophilic Esophagitis JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Patel, A. J., Fuentebella, J., Gernez, Y., Nguyen, T., Bass, D., Berquist, W., Cox, K., Sibley, E., Kerner, J., Nadeau, K. 2010; 51 (3): 290-294

    Abstract

    The aim of the study was to investigate whether eosinophils have increased human leukocyte antigen (HLA)-DR expression in subjects with eosinophilic esophagitis (EoE) compared with controls.Patients who were undergoing an upper endoscopy with biopsies for suspected gastroesophageal reflux disease (GERD) or EoE at Lucile Packard Children's Hospital were enrolled. In total, the blood and tissue samples of 10 healthy controls (HC), 11 subjects with GERD, and 10 with EoE were studied. Multiple tissue staining to identify eosinophils (via eosinophil cationic protein-clone EG2) and major histocompatibility complex class II cell surface receptors (via HLA-DR) was performed via immunohistochemistry. The peripheral blood was analyzed using flow cytometry to detect eosinophil HLA-DR expression among these subjects.In the tissue, a greater proportion of eosinophils expressed HLA-DR among the subjects with EoE (mean 0.83 +/- 0.14, n = 9) relative to those with GERD (mean 0.18 +/- 0.19, n = 8, P < 0.01) and HC (mean 0.18 +/- 0.13, n = 6, P < 0.01). In total, 6 participants (4 HC subjects and 2 subjects with GERD) did not have any eosinophils identified on tissue staining and were unable to be included in the present statistical analysis. In the blood, there was no statistically significant difference in eosinophil HLA-DR expression among HC subjects (mean 415 +/- 217, n = 6), subjects with GERD (mean 507 +/- 429, n = 2), and those with EoE (mean 334 +/- 181, n = 6).These data demonstrate that the eosinophils from the esophagus of subjects with EoE have increased HLA-DR expression within this tissue.

    View details for DOI 10.1097/MPG.0b013e3181e083e7

    View details for Web of Science ID 000281453500008

    View details for PubMedID 20639774

  • Epoprostenol-associated pneumonitis: Diagnostic use of a T-cell proliferation assay JOURNAL OF HEART AND LUNG TRANSPLANTATION Kudelko, K. T., Nadeau, K., Leung, A. N., Liu, J., Haddad, F., Zamanian, R. T., Perez, V. D. 2010; 29 (9): 1071-1075
  • Increased Number of Regulatory T Cells in Children With Eosinophilic Esophagitis JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Fuentebella, J., Patel, A., Nguyen, T., Sanjanwala, B., Berquist, W., Kerner, J. A., Bass, D., Cox, K., Hurwitz, M., Huang, J., Nguyen, C., Quiros, J. a., Nadeau, K. 2010; 51 (3): 283-289

    Abstract

    There are limited data on the role of regulatory T cells (Treg) in the disease pathology of eosinophilic esophagitis (EoE). We tested the differences in Treg in subjects with EoE compared with those with gastroesophageal reflux disease (GERD) and healthy controls (HC).Pediatric patients evaluated by endoscopy were recruited for our study. Participants were categorized into 3 groups: EoE, GERD, and HC. RNA purified from esophageal biopsies were used for real-time quantitative polymerase chain reaction assays and tested for forkhead box P3 (FoxP3) mRNA expression. Treg were identified as CD4+CD25hiCD127lo cells in peripheral blood and as CD3+/FoxP3+cells in esophageal tissue.Forty-eight subjects were analyzed by real-time quantitative polymerase chain reaction: EoE (n = 33), GERD (n = 7), and HC (n = 8). FoxP3 expression was higher by up to 1.5-fold in the EoE group compared with the GERD and HC groups (P < 0.05). Protein levels of FoxP3 in blood and tissue were then investigated in 21 subjects: EoE (n = 10), GERD (n = 6), and HC (n = 5). The percentage of Treg and their subsets in peripheral blood were not significant between groups (P > 0.05). The amount of Treg in esophageal tissue was significantly greater in the EoE group (mean 10.7 CD3+/FoxP3+cells/high power field [HPF]) compared with the other groups (GERD, mean 1.7 CD3+/FoxP3+cells/HPF and HC, mean 1.6 CD3+/FoxP3+cells/HPF) (P < 0.05).We show that Treg are increased in esophageal tissue of EoE subjects compared with GERD and HC subjects. The present study illustrates another possible mechanism involved in EoE that implicates impairment of immune homeostasis.

    View details for DOI 10.1097/MPG.0b013e3181e0817b

    View details for Web of Science ID 000281453500007

    View details for PubMedID 20639775

  • Epoprostenol-associated pneumonitis: diagnostic use of a T-cell proliferation assay. journal of heart and lung transplantation Kudelko, K. T., Nadeau, K., Leung, A. N., Liu, J., Haddad, F., Zamanian, R. T., de Jesus Perez, V. 2010; 29 (9): 1071-1075

    Abstract

    We describe a case of severe drug-induced interstitial pneumonitis in a woman with idiopathic pulmonary arterial hypertension receiving epoprostenol confirmed by a drug T-cell proliferation assay. Proliferation assays were completed in our patient and in a healthy control. Isolated T cells were incubated with CD3-depleted peripheral blood mononuclear cells and then stimulated to proliferate with (3)H-thymidine in the presence of epoprostenol, other prostanoid analogs, and controls. A significant (p < 0.001) T-cell proliferation response occurred in our patient in the presence of epoprostenol alone. There was a trend towards an increased T-cell response to treprostinil but this was statistically insignificant. There was no significant T-cell response to the diluent alone, normal saline, iloprost, or alprostadil. There was no significant proliferation to any drug in the healthy control. Hence, a drug T-cell proliferation assay confirmed that epoprostenol can rarely incite a profound inflammatory response in the pulmonary interstitium.

    View details for DOI 10.1016/j.healun.2010.04.023

    View details for PubMedID 20627625

    View details for PubMedCentralID PMC2926193

  • Individual Variation in the Germline Ig Gene Repertoire Inferred from Variable Region Gene Rearrangements JOURNAL OF IMMUNOLOGY Boyd, S. D., Gaeta, B. A., Jackson, K. J., Fire, A. Z., Marshall, E. L., Merker, J. D., Maniar, J. M., Zhang, L. N., Sahaf, B., Jones, C. D., Simen, B. B., Hanczaruk, B., Nguyen, K. D., Nadeau, K. C., Egholm, M., Miklos, D. B., Zehnder, J. L., Collins, A. M. 2010; 184 (12): 6986-6992

    Abstract

    Individual variation in the Ig germline gene repertoire leads to individual differences in the combinatorial diversity of the Ab repertoire, but the study of such variation has been problematic. The application of high-throughput DNA sequencing to the study of rearranged Ig genes now makes this possible. The sequencing of thousands of VDJ rearrangements from an individual, either from genomic DNA or expressed mRNA, should allow their germline IGHV, IGHD, and IGHJ repertoires to be inferred. In addition, where previously mere glimpses of diversity could be gained from sequencing studies, new large data sets should allow the rearrangement frequency of different genes and alleles to be seen with clarity. We analyzed the DNA of 108,210 human IgH chain rearrangements from 12 individuals and determined their individual IGH genotypes. The number of reportedly functional IGHV genes and allelic variants ranged from 45 to 60, principally because of variable levels of gene heterozygosity, and included 14 previously unreported IGHV polymorphisms. New polymorphisms of the IGHD3-16 and IGHJ6 genes were also seen. At heterozygous loci, remarkably different rearrangement frequencies were seen for the various IGHV alleles, and these frequencies were consistent between individuals. The specific alleles that make up an individual's Ig genotype may therefore be critical in shaping the combinatorial repertoire. The extent of genotypic variation between individuals is highlighted by an individual with aplastic anemia who appears to lack six contiguous IGHD genes on both chromosomes. These deletions significantly alter the potential expressed IGH repertoire, and possibly immune function, in this individual.

    View details for DOI 10.4049/jimmunol.1000445

    View details for Web of Science ID 000278516700047

    View details for PubMedID 20495067

  • Human Basophils: New Mechanisms Of Action And Role In Food Allergy 66th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) Gernez, Y., Tirouvanziam, R., Yu, G., Reshamwala, N., Tsai, M., GALLI, S. J., Herzenberg, L. A., Nadeau, K. C. MOSBY-ELSEVIER. 2010: AB86–AB86
  • Epigenetic Modifications of Foxp3 Locus are Associated with Asthma in Children exposed to High Levels of Ambient Air Pollution 66th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI) McDonald-Hyman, C., Tager, I., Nadeau, K. MOSBY-ELSEVIER. 2010: AB356–AB356
  • Bradykinin Inhibitors in Hereditary Angioedema J Angioedema Nelson K, Nadeau KC 2010; 1 (1): 27-30
  • Ambient Air Pollution Impairs Regulatory T-Cell Function in Asthma. J Allergy Clin Immunol Nadeau KC, Hyman-McDonald C, Hammond K, Balmes J, Tager I 2010; 126 (4): 845-852
  • Increased Number of Regulatory T Cells in Children with Eosinophilic Esophagitis. J Pediatr Gastroenterol Nutri Fuentebella J, Patel A, Nguyen T, Sanjanwala B, Berquist W, Kerner KA, Bass D, Cox K, Hurwitz M, Hung J, Nguyen C, Quiros JA, Nadeau KC 2010; 51 (3): 283-9
  • Epoprostenol-Associated Pneumonitis: Diagnostic Use of a T Cell Proliferation Assay J Heart Lung Transplant Kudelko KT, De Jesus Perez V, Jaddad F, Zamanian RG, Nadeau KC, Leung A, Liu J 2010; 29 (9): 1071-5
  • Increased HLA-DR Expression on Tissue Eosinophils in Eosinophilic Esophagitis. J Pediatr Gastroenterol Nutr Patel AJ, Fuentebella J, Gernez Y, Nguyen T, Bass D, Berquist W, Cox K, Sibley E, Kerner J, Nadeau KC 2010; 51 (3): 290-4
  • TSLP directly impairs pulmonary Treg function: association with aberrant tolerogenic immunity in asthmatic airway. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology Nguyen, K. D., Vanichsarn, C., Nadeau, K. C. 2010; 6 (1): 4-?

    Abstract

    Even though thymic stromal lymphopoietin (TSLP) has been implicated in the development of allergic inflammation, its influence on immune tolerance mediated by regulatory T cells (Treg) have not been explored. We aimed to dissect the influence of TSLP on immunosuppressive activities of Treg and its potential consequences in human allergic asthma.In vitro culture system was utilized to study the effects of TSLP on human Treg. The functional competency of pulmonary Treg from a cohort of 15 allergic asthmatic, 15 healthy control, and 15 non-allergic asthmatic subjects was also evaluated by suppression assays and flow cytometric analysis.Activated pulmonary Treg expressed TSLP-R and responded to TSLP-mediated activation of STAT5. TSLP directly and selectively impaired IL-10 production of Treg and inhibited their suppressive activity. In human allergic asthma, pulmonary Treg exhibited a significant decrease in suppressive activity and IL-10 production compared to healthy control and non-allergic asthmatic counterparts. These functional alterations were associated with elevated TSLP expression in bronchoalveolar lavage fluid (BAL) of allergic asthmatic subjects. Furthermore, allergic asthmatic BAL could suppress IL-10 production by healthy control pulmonary Treg in a TSLP-dependent manner.These results provide the first evidences for a direct role of TSLP in the regulation of suppressive activities of Treg. TSLP mediated inhibition of Treg function might present a novel pathologic mechanism to dampen tolerogenic immune responses in inflamed asthmatic airway.

    View details for DOI 10.1186/1710-1492-6-4

    View details for PubMedID 20230634

  • Mechanistic Studies of Tolerance in sublingual innmunotherapy (SLIT) patients with Dermatophagoides farinae and Timothy grass allergy 10th Annual Meeting of the Federation-of-Clinical-Immunology-Societies Reshamwala, N., Swamy, R., Berquist, S., Nguyen, T., Hoyte, E., Vissamsetti, S., Sivagnanasundaram, A., Saper, V., Hwang, P., Moss, R., Nadeau, K. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2010: S65–S65
  • Transcription Factors as Disease Indicators in Eosinophilic Esophagitis 10th Annual Meeting of the Federation-of-Clinical-Immunology-Societies Nguyen, T., Gernez, Y., Fuentella, J., Patel, A., Tirouvanziam, R., Reshamwala, N., Saper, V., Bass, D., Berquist, W., Kerner, J., Nadeau, K. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2010: S81–S82
  • Eotaxin and FGF enhance signaling through an extracellular signal-related kinase (ERK)-dependent pathway in the pathogenesis of Eosinophilic esophagitis. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology Huang, J. J., Joh, J. W., Fuentebella, J., Patel, A., Nguyen, T., Seki, S., Hoyte, L., Reshamwala, N., Nguyen, C., Quiros, A., Bass, D., Sibley, E., Berquist, W., Cox, K., Kerner, J., Nadeau, K. C. 2010; 6 (1): 25-?

    Abstract

    Eosinophilic esophagitis (EoE) is characterized by the inflammation of the esophagus and the infiltration of eosinophils into the esophagus, leading to symptoms such as dysphagia and stricture formation. Systemic immune indicators like eotaxin and fibroblast growth factor were evaluated for possible synergistic pathological effects. Moreover, blood cells, local tissue, and plasma from EoE and control subjects were studied to determine if the localized disease was associated with a systemic effect that correlated with presence of EoE disease.Real-time polymerase chain reaction from peripheral blood mononuclear cells (PBMC), immunohistochemistry from local esophageal biopsies, fluid assays on plasma, and fluorescence-activated cell sorting on peripheral blood cells from subjects were used to study the systemic immune indicators in newly diagnosed EoE (n = 35), treated EoE (n = 9), Gastroesophageal reflux disease (GERD) (n = 8), ulcerative colitis (n = 5), Crohn's disease (n = 5), and healthy controls (n = 8).Of the transcripts tested for possible immune indicators, we found extracellular signal-regulated kinase (ERK), Bcl-2, bFGF (basic fibroblast growth factor), and eotaxin levels were highly upregulated in PBMC and associated with disease presence of EoE. Increased FGF detected by immunohistochemistry in esophageal tissues and in PBMC was correlated with low levels of pro-apoptotic factors (Fas, Caspase 8) in PBMC from EoE subjects. Plasma-derived bFGF was shown to be the most elevated and most specific in EoE subjects in comparison to healthy controls and disease control subjects.We describe for the first time a possible mechanism by which increased FGF is associated with inhibiting apoptosis in local esophageal tissues of EoE subjects as compared to controls. Eotaxin and FGF signaling pathways share activation through the ERK pathway; together, they could act to increase eosinophil activation and prolong the half-life of eosinophils in local tissues of the esophagus in EoE subjects.

    View details for DOI 10.1186/1710-1492-6-25

    View details for PubMedID 20815913

  • Measurement and Clinical Monitoring of Human Lymphocyte Clonality by Massively Parallel V-D-J Pyrosequencing SCIENCE TRANSLATIONAL MEDICINE Boyd, S. D., Marshall, E. L., Merker, J. D., Maniar, J. M., Zhang, L. N., Sahaf, B., Jones, C. D., Simen, B. B., Hanczaruk, B., Nguyen, K. D., Nadeau, K. C., Egholm, M., Miklos, D. B., Zehnder, J. L., Fire, A. Z. 2009; 1 (12)

    Abstract

    The complex repertoire of immune receptors generated by B and T cells enables recognition of diverse threats to the host organism. In this work, we show that massively parallel DNA sequencing of rearranged immune receptor loci can provide direct detection and tracking of immune diversity and expanded clonal lymphocyte populations in physiological and pathological contexts. DNA was isolated from blood and tissue samples, a series of redundant primers was used to amplify diverse DNA rearrangements, and the resulting mixtures of barcoded amplicons were sequenced using long-read ultra deep sequencing. Individual DNA molecules were then characterized on the basis of DNA segments that had been joined to make a functional (or nonfunctional) immune effector. Current experimental designs can accommodate up to 150 samples in a single sequence run, with the depth of sequencing sufficient to identify stable and dynamic aspects of the immune repertoire in both normal and diseased circumstances. These data provide a high-resolution picture of immune spectra in normal individuals and in patients with hematological malignancies, illuminating, in the latter case, both the initial behavior of clonal tumor populations and the later suppression or re-emergence of such populations after treatment.

    View details for DOI 10.1126/scitranslmed.3000540

    View details for Web of Science ID 000277263200001

    View details for PubMedID 20161664

  • Impaired IL-10-dependent Induction of Tolerogenic Dendritic Cells by CD4(+)CD25(hi)CD127(lo/-) Natural Regulatory T Cells in Human Allergic Asthma AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Nguyen, K. D., Vanichsarn, C., Nadeau, K. C. 2009; 180 (9): 823-833

    Abstract

    Tolerogenic dendritic cells and natural regulatory T cells have been implicated in the process of infectious tolerance in human allergic asthma. However, the significance of the influence of natural regulatory T cells on tolerogenic dendritic cells in the disease has not been investigated.We aimed to characterize the mechanism of induction of the tolerogenic phenotype in circulating blood dendritic cells by allergic asthmatic natural regulatory T cells.The study was performed in a cohort of 21 subjects with allergic asthma, 21 healthy control subjects, and 21 subjects with nonallergic asthma. We cultured blood dendritic cells with natural regulatory T cells to study the induction of tolerogenic dendritic cells. Flow cytometry and proliferation assays were employed to analyze phenotype and function of dendritic cells as well as IL-10 production from natural regulatory T cells.Dendritic cells cultured with natural regulatory T cells up-regulated IL-10, down-regulated costimulatory molecules, and stimulated the proliferation of CD4(+)CD25(-) effector T cells less potently. Allergic asthmatic natural regulatory T cells were significantly less efficient in inducing this tolerogenic phenotype of dendritic cells compared with healthy control and nonallergic asthmatic counterparts. Furthermore, this defective function of natural regulatory T cells was associated with their decreased IL-10 expression, disease severity, and could be reversed by oral corticosteroid therapy.These results provided the first evidences of impaired induction of tolerogenic dendritic cells mediated by natural regulatory T cells in human allergic asthma.

    View details for DOI 10.1164/rccm.200905-0761OC

    View details for Web of Science ID 000271215500006

    View details for PubMedID 19679691

  • Neonatal Alloimmune Thrombocytopenia and Neutropenia Associated With Maternal Human Leukocyte Antigen Antibodies PEDIATRIC BLOOD & CANCER Gramatges, M. M., Fani, P., Nadeau, K., Pereira, S., Jeng, M. R. 2009; 53 (1): 97-99

    Abstract

    Neonatal thrombocytopenia or neutropenia may result from passive transfusion of maternally derived antibodies. Antibodies against platelet antigens are commonly associated with neonatal alloimmune thrombocytopenia (NAIT), and anti-neutrophil antibodies are frequently identified in alloimmune neonatal neutropenia (ANN). Combined alloimmune cytopenias in the newborn are rarely reported; even fewer reports document human leukocyte antigen (HLA) antibodies as a potential cause of neonatal thrombocytopenia or neutropenia. We describe neutropenia and thrombocytopenia in a newborn associated with markedly elevated maternal HLA antibodies in the absence of anti-neutrophil or anti-platelet antibodies to highlight consideration of HLA antibodies in the pathogenesis of ANN and NAIT.

    View details for DOI 10.1002/pbc.21979

    View details for Web of Science ID 000266186200021

    View details for PubMedID 19229975

  • Regulatory T cell dysfunction in subjects with common variable immunodeficiency complicated by autoimmune disease CLINICAL IMMUNOLOGY Yu, G. P., Chiang, D., Song, S. J., Hoyte, E. G., Huang, J., Vanishsarn, C., Nadeau, K. C. 2009; 131 (2): 240-253

    Abstract

    Approximately 25% of subjects with common variable immunodeficiency (CVID) develop autoimmune disease. We analyzed T cell subsets, specifically regulatory T cells along with B cell subsets to determine whether there were changes in regulatory T cells which would correlate with the autoimmune disease clinical phenotype in CVID subjects. We hypothesized that regulatory T cell (CD4+CD25hiCD127lo) suppressive function would be impaired in CVID subjects with autoimmune disease. Using purified, sorted Treg from CVID subjects (n=14) and from healthy controls (HC, n=5) in standard suppression assays, we found the suppressive function of Treg from CVID subjects with autoimmune disease (CVID w/ AI, n=8) to be significantly attenuated compared to CVID subjects with no autoimmune disease (CVID w/o AI, n=6) and to HC (n=5). A number of proteins associated with Treg function were decreased in expression as detected through immunofluorescent antibody via flow cytometry (mean fluorescence intensity (MFI) of FoxP3, Granzyme A, XCL1, pSTAT5, and GITR in Treg was significantly lower (by up to 3 fold) in CVID w/ AI compared to CVID w/o AI and HC. Furthermore, a statistically significant correlation was found between intracellular MFI of FoxP3, Granzyme A, and pSTAT5 in Treg and the degree of Treg dysfunction. These results suggest that attenuation of Treg function is associated with autoimmune disease in CVID subjects and may contribute to autoimmune pathogenesis.

    View details for DOI 10.1016/j.clim.2008.12.006

    View details for Web of Science ID 000265420000007

    View details for PubMedID 19162554

  • Selective deregulation in chemokine signaling pathways of CD4(+)CD25(hi)CD127(lo/-) regulatory T cells in human allergic asthma JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Nguyen, K. D., Vanichsarn, C., Fohner, A., Nadeau, K. C. 2009; 123 (4): 933-939

    Abstract

    CD4+CD25(hi)CD127(lo)/(-) regulatory T cells have been suggested to be critical regulators of inflammatory processes in allergic asthma. Recent studies reported a selective decrease in the frequency of regulatory T cells in the bronchoalveolar lavage fluid of allergic asthmatic (AA) subjects, prompting the possibility of defective recruitment of these cells to the airway in response to chemokines produced during asthmatic inflammation.This study aimed to characterize the chemotactic profile of circulating regulatory T cells in AA subjects in response to chemokines abundantly produced in airway inflammation, such as CCL1, CCL17, and CCL22.The study was performed in a cohort of 26 AA, 16 healthy control, and 16 non-AA subjects. We used chemotaxis assays to evaluate cell migration, flow cytometry to examine chemokine receptor expression, and phospho-ELISA to study consequent signaling pathways in regulatory T cells.Regulatory T cells, but not CD4+CD25(-)T cells, from AA subjects showed decreased chemotactic responses, specifically to CCL1, in comparison with their healthy control and non-AA counterparts. Decreased CCL1-mediated chemotaxis in AA regulatory T cells was associated with decreased phosphorylation of protein kinase B (AKT), a protein involved in chemokine intracellular signaling. Furthermore, the decreased chemotactic response to CCL1 in AA regulatory T cells significantly correlated with asthma severity and decreased pulmonary function in AA subjects.These results provide the first evidence of dysfunction in the chemokine signaling pathway in AA regulatory T cells.

    View details for DOI 10.1016/j.jaci.2008.11.037

    View details for Web of Science ID 000265058600023

    View details for PubMedID 19152963

  • Identifying Eosinophilic Esophagitis through Evaluation of Plasma Biomarkers 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology Joh, J., Huang, J., Nguyen, T., Vishwaanath, N., Patel, A., Fuentebella, J., Saper, V., Kerner, J., Cox, K., Berquist, W., Nadeau, K. MOSBY-ELSEVIER. 2009: S169–S169
  • Natural Regulatory T Cell Dysfunction in Subjects with Common Variable Immunodeficiency Complicated by Autoimmune Disease is associated with activation of the AkT-mTOR pathway 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology Yu, G. P., Berquist, S. W., Huang, J. J., Martinez, J., Hoyte, E. G., Vanichsarn, C. T., Nadeau, K. C. MOSBY-ELSEVIER. 2009: S264–S264
  • Correlation of Phenotypic Expression of Milk Sensitivity in Young Patients by the Simultaneous Determination of IgE to Whole Milk Extract and Milk Specific Allergenic Proteins 65th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology Saper, V., Innerst, D., Nadeau, K., Hoyte, E., Vanichsarn, C., Zychlinsky, E. MOSBY-ELSEVIER. 2009: S30–S30
  • T Lymphocytes and Its Subsets in Transplanted Small Bowel Treated with Alemtuzumab (Campath-1H) Proc XI Int Small Bowel Transplant Sym Fuentebella J, Seki S, Nadeau KC, Castillo RO 2009; Dec: 37-42
  • T lymphocytes and Its Subsets in Transplanted Small Bowel Treated with Alemtuzumab (Campath-1H) 11th International Symposium on Small Bowel Transplant Fuentebella, J., Seki, S., Nadeau, K., Castillo, R. O. MEDIMOND S R L. 2009: 42–47
  • Idiopathic neutropenia of childhood is associated with Fas/FasL expression CLINICAL IMMUNOLOGY Nadeau, K. C., Callejas, A., Wong, W. B., Joh, J. W., Cohen, H. J., Jeng, M. R. 2008; 129 (3): 438-447

    Abstract

    Idiopathic neutropenia (IN) in children is characterized by decreased neutrophil counts (<1500/microl), can be acute or chronic (greater than 6 months duration). The pathophysiology is not well understood; therefore, potential mechanisms of pediatric IN were investigated. An increase in Fas transcripts in neutrophils of IN patients compared to age-matched healthy control (HC) neutrophils was observed (p<0.005). Increased expression of Fas protein was found in IN neutrophils, while Fas surface expression on other immune cells was similar. Plasma from acute IN patients had higher protein levels of soluble FasL than chronic IN patients. When HC neutrophils were incubated in plasma from IN patients, greater rates of apoptosis were observed. Biochemical studies suggest the apoptotic factor(s) in plasma is heat-sensitive, non-IgG, and 12-50 kD protein. Addition of anti-sFasL blocking antibodies to patient plasma caused a statistically significant decrease in neutrophil apoptosis. These studies show that the Fas/FasL pathway could be associated with neutrophil apoptosis in childhood IN.

    View details for DOI 10.1016/j.clim.2008.08.006

    View details for Web of Science ID 000261011100007

    View details for PubMedID 18819843

    View details for PubMedCentralID PMC4161459

  • XCL1 enhances regulatory activities of CD4(+)CD25(high)CD127(low/-) T cells in human allergic asthma JOURNAL OF IMMUNOLOGY Nguyen, K. D., Fohner, A., Booker, J. D., Dong, C., Krensky, A. M., Nadeau, K. C. 2008; 181 (8): 5386-5395

    Abstract

    Chemokine-mediated recruitment of regulatory cell subsets to the airway during inflammation and enhancement of their activities are potential strategies for therapeutic development in allergic asthma (AA). In this study, we aim to explore the role of XCL1, a chemokine associated with immune suppression and allergy, on CD4(+)CD25(high)CD127(low/-) regulatory T cell (Treg) function in AA. Flow cytometry and PCR analysis showed a reduction in XCL1 and XCR1 expression in AA Treg compared with healthy control and nonallergic asthmatic counterparts. This reduction in XCL1 expression was associated with the suboptimal regulatory function of Treg in AA. Interestingly, incubation with recombinant human XCL1 significantly increased Treg-mediated suppression and cytotoxicity by up-regulating expression of XCL1 and chief effector molecules of Treg function. Altogether, these results suggest an association between dysregulated XCL1 expression and reduced Treg activities in AA, as well as a potential role of XCL1 in reversing defective Treg function in the disease.

    View details for Web of Science ID 000260025300030

    View details for PubMedID 18832695

  • Increased cytotoxicity of CD4(+) invariant NKT cells against CD4(+)CD25(hi)CD127(lo/-) regulatory T cells in allergic asthma EUROPEAN JOURNAL OF IMMUNOLOGY Nguyen, K. D., Vanichsarn, C., Nadeau, K. C. 2008; 38 (7): 2034-2045

    Abstract

    CD4+CD25(hi)CD127(lo/-) regulatory T cells (Treg) have been implicated in the resolution of asthma-associated inflammation while the opposite role of CD4+ invariant NKT (iNKT) cells has been the subject of recent investigations. Studies here focused on mechanisms of interaction between CD4+ iNKT cells and Treg to further explore their roles in allergic asthma (AA). Flow cytometry analysis revealed a significant increase in the expression of the natural cytotoxicity receptors NKp30 and NKp46 by CD4+ iNKT cells in AA subjects compared to healthy controls (HC) and non-allergic asthmatics (NA). Subsequent intracellular staining showed that CD4+ iNKT cells also expressed higher levels of granzyme B and perforin in AA than HC. In in vitro killing assays, AA CD4+ iNKT cells selectively killed autologous Treg, but not CD4+CD25- T cells, more potently than HC and NA counterparts. This increased cytotoxicity positively correlated with asthma severity and granzyme B/perforin expression of CD4+ iNKT cells. Furthermore, it could be abrogated by either inhibition of the granzyme B-/perforin-dependent cell death pathway or oral corticosteroid administration. Altogether, these findings suggest that increased cytotoxicity of CD4+ iNKT cells against Treg might contribute to dysfunctional cellular interactions in AA.

    View details for DOI 10.1002/eji.200738082

    View details for Web of Science ID 000257826300027

    View details for PubMedID 18581330

  • A novel mutation associated with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY Bhui, R. D., Lewis, D. B., Nadeau, K. C. 2008; 100 (2): 169-169

    View details for Web of Science ID 000253136500012

    View details for PubMedID 18320920

  • Safety of omalizumab treatment in children (> 4 years) with high serum IgE and severe atopic dermatitis and food allergy 64th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology Iyengar, S. R., Hoyte, E. G., Loza, A., Bonaccorso, S., Umetsu, D. T., Nadeau, K. C. MOSBY-ELSEVIER. 2008: S32–S32
  • Altered phosphorylated signal transducer and activator of transcription profile of CD4(+)CD161(+) T cells in asthma: Modulation by allergic status and oral corticosteroids JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Gernez, Y., Tirouvanziam, R., Nguyen, K. D., Herzenberg, L. A., Krensky, A. M., Nadeau, K. C. 2007; 120 (6): 1441-1448

    Abstract

    Asthma is a complex immunologic disorder linked to altered cytokine signaling.We tested whether asthmatic patients showed any change in cytokine-dependent signal transducer and activator of transcription (STAT) levels, focusing on the central/effector-memory CD4(+)CD161(+) subset, which represents 15% to 25% of circulating T cells.We quantified intracellular levels of active phosphorylated STAT (phospho-STAT) 1, 3, 5, and 6 by means of flow cytometry, without any activation or expansion.Baseline phospho-STAT1 and phospho-STAT6 levels were increased in CD4(+)CD161(+) T cells from asthmatic patients compared with those from healthy control subjects (by 10- and 8-fold, respectively). This asthma-associated alteration was both subset specific because no change was seen in CD4(+)CD161(-)CD25(+) (regulatory T cells) and CD4(+)CD161(-)CD25(-) subsets and isoform specific because phospho-STAT5 and phospho-STAT3 levels were unchanged. Among asthmatic patients, phospho-STAT1 and phospho-STAT6 levels correlated negatively with each other, suggesting antagonistic regulation. Oral corticosteroid (OCS) treatment significantly decreased phospho-STAT6 and IL-4 levels but not phospho-STAT1 levels. Disease parameters showing significant correlations with phospho-STAT1, phospho-STAT6, or both included age at onset, plasma IgE levels, and levels of the T(H)2 cytokines IL-4 and IL-10 and the T(H)1 cytokine IL-2. Overall, combined phospho-STAT1 and phospho-STAT6 measurements showed excellent predictive value for identifying (1) asthmatic patients versus healthy control subjects, (2) allergic versus nonallergic asthmatic patients, and (3) asthmatic patients taking versus those not taking OCSs.Baseline changes in phospho-STAT1 and phospho-STAT6 levels in blood CD4(+)CD161(+) T cells identify asthmatic patients and mirror their allergic status and response to OCSs.These results confirm the pathologic importance of activated STAT1 and STAT6 in asthma and suggest their potential use as clinical biomarkers.

    View details for DOI 10.1016/j.jaci.2007.08.012

    View details for Web of Science ID 000251653800029

    View details for PubMedID 17919711

  • Role of Fas/FasL pathway in pediatric idiopathic neutropenia 49th Annual Meeting of the American-Society-of-Hematology Joh, J. W., Callejas, A., Wong, W., Cohen, H. J., Nadeau, K., Jeng, M. AMER SOC HEMATOLOGY. 2007: 966A–967A
  • Lymphotactin improves treg function in asthmatics via the STAT5 pathway 7th Annual Meeting of the Federation-of-Clinical-Immunology-Societies Fohner, A., Nguyen, K., Krensky, A. M., Nadeau, K. C. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2007: S77–S77
  • Identification of specific chemokines and apoptosis molecules in pediatric idiopathic neutropenia. 48th Annual Meeting of the American-Society-of-Hematology Callejas, A., Nadeau, K., Bakshi, K., Wong, W., Carroll, T., Lau, K., Yang, Y., Schilling, J., Clayberger, C., Krensky, A., Jeng, M. AMER SOC HEMATOLOGY. 2006: 40B–40B
  • Cutting edge: Decreased accumulation and regulatory function of CD4(+)CD25(high) T cells in human STAT 5b deficiency JOURNAL OF IMMUNOLOGY Cohen, A. C., Nadeau, K. C., Tu, W., Hwa, V., Dionis, K., Bezrodnik, L., Teper, A., Gaillard, M., Heinrich, J., Krensky, A. M., Rosenfeld, R. G., Lewis, D. B. 2006; 177 (5): 2770-2774

    Abstract

    We show that STAT5b is important for the in vivo accumulation of CD4+ CD25(high) T cells with regulatory cell function. A patient homozygous for a missense A630P STAT5b mutation displayed immune dysregulation and decreased numbers of CD4+ CD25(high) T cells. STAT5b(A630P/A630P) CD4+ CD25(high) T cells had low expression of forkhead box P3 and an impaired ability to suppress the proliferation of or to kill CD4+ CD25- T cells. Expression of CD25, a component of the high-affinity IL-2R, was also reduced in response to IL-2 or after in vitro propagation. The impact of the STAT5b mutation was selective in that IL-2-mediated up-regulation of the common gamma-chain cytokine receptor and perforin, and activation-induced expressions of CD154 and IFN-gamma were normal. These results indicate that STAT5b propagates an important IL-2-mediated signal for the in vivo accumulation of functional regulatory T cells.

    View details for Web of Science ID 000240002800007

    View details for PubMedID 16920911

  • Lgl1 is suppressed in oxygen toxicity animal models of bronchopulmonary dysplasia and normalizes during recovery in air PEDIATRIC RESEARCH Nadeau, K., Jankov, R. P., Tanswell, A. K., Sweezey, N. B., Kaplan, F. 2006; 59 (3): 389-395

    Abstract

    Bronchopulmonary dysplasia (BPD), a major cause of morbidity in premature infants, is characterized by arrest of lung growth and inhibited alveologenesis. We had earlier cloned late-gestation lung 1 (LGL1), a glucocorticoid (GC)-induced, developmentally regulated gene in lung mesenchyme, and showed that reduced levels of late-gestation lung 1 protein (lgl1) inhibit lung branching. Maximal fetal expression of LGL1 is concordant with the onset of alveolar septation, suggesting an additional role for lgl1 in alveologenesis. At postnatal d 7, during the period of maximal septation in postnatal rat lung, lgl1 concentrates at the tips of budding secondary alveolar septa. We studied two models of impaired postnatal alveologenesis generated by exposure of newborn rats to 60% O2 for 2 wk or 95% O2 for 1 wk. A profound decrease of lgl1 expression with oxygen exposure was observed in both animal models. Animals exposed to 95% O2 for 1 wk recovered in air over a 3-wk period, associated with normalization of lgl1 levels. Changes in lung levels of alpha-actin (a marker of myofibroblast differentiation associated with alveologenesis) and the mesenchymal marker vimentin were significant but less marked. Our findings support a role for lgl1 in postnatal lung development. We speculate that deficiency of lgl1 contributes to the arrested alveolar partitioning observed in BPD and that recovery is associated with normalization of lgl1 levels.

    View details for DOI 10.1203/01.pdr.0000198819.81785.f1

    View details for Web of Science ID 000235626700009

    View details for PubMedID 16492977

  • Outcomes in twelve T-B+Nk+ SCID patients treated with HSCT. 6th Annual Meeting of the Federation-of-Clinical-Immunology-Societies Yu, G., Nadeau, K., Berk, D., Jun, I., Tsao, G., Lewis, D., Krensky, A., Umetsu, D., Mort, C. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2006: S135–S136
  • Successful conversion from conventional immunosuppression to anti-CD154 monoclonal antibody costimulatory molecule blockade in rhesus renal allograft recipients Annual Meeting of the American-Society-of-Transplantation Cho, C. S., Burkly, L. C., Fechner, J. H., Kirk, A. D., Oberley, T. D., Dong, Y. C., Brunner, K. G., Peters, D., Tenhoor, C. N., Nadeau, K., Yagci, G., Ishido, N., Schultz, J. M., Tsuchida, M., Hamawy, M. M., Knechtle, S. J. LIPPINCOTT WILLIAMS & WILKINS. 2001: 587–97

    Abstract

    Several conventional forms of immunosuppression have been shown to antagonize the efficacy of anti-CD154 monoclonal antibody- (mAb) based costimulatory molecule blockade immunotherapy. Our objective was to determine if allograft recipients treated with a conventional immunosuppressive regimen could be sequentially converted to anti-CD154 mAb monotherapy without compromising graft survival.Outbred juvenile rhesus monkeys underwent renal allotransplantation from MHC-disparate donors. After a 60-day course of triple therapy immunosuppression with steroids, cyclosporine, and mycophenolate mofetil, monkeys were treated with: (1) cessation of all immunosuppression (control); (2) seven monthly doses of 20 mg/kg hu5C8 (maintenance), or; (3) 20 mg/kg hu5C8 on posttransplant days 60, 61, 64, 71, 79, and 88 followed by five monthly doses (induction+maintenance). Graft rejection was defined by elevation in serum creatinine>1.5 mg/dl combined with histologic evidence of rejection.Graft survival for the three groups were as follows: group 1 (control): 70, 75, >279 days; group 2 (maintenance): 83, 349, >293 days, and; group 3 (induction+maintenance): 355, >377, >314 days. Acute rejection developing in two of four monkeys after treatment with conventional immunosuppression was successfully reversed with intensive hu5C8 monotherapy.Renal allograft recipients can be successfully converted to CD154 blockade monotherapy after 60 days of conventional immunosuppression. An induction phase of anti-CD154 mAb appears to be necessary for optimal conversion. Therefore, although concurrent administration of conventional immunosuppressive agents including steroids and calcineurin inhibitors has been shown to inhibit the efficacy of CD154 blockade, sequential conversion from these agents to CD154 blockade appears to be effective.

    View details for Web of Science ID 000170968400006

    View details for PubMedID 11544416

  • Inhibition of CD40 ligand (CD154) in the treatment of factor VIII inhibitors. Haematologica Ewenstein, B. M., Hoots, W. K., Lusher, J. M., DiMichele, D., White, G. C., Adelman, B., Nadeau, K. 2000; 85 (10): 35-39

    Abstract

    The development of persistent, high titer inhibitors represents a serious complication of the treatment of patients with severe hemophilia A. Elimination of these inhibitory antibodies is usually attempted through repeated administration of high doses of factor VIII. Such regimens are costly, time-consuming and often fail when the inhibitor is of very high titer or of longstanding duration. A potential alternative approach to inhibit the production of antifactor VIII antibodies is blockade of the T-cell/B-cell collaboration that is required to generate humoral responses. One cognate receptor pair that is required for T-cell-dependent B-cell activation consists of CD40, which is expressed on B-lymphocytes and other antigen presenting cells, and CD40 ligand (CD40L, CD154), which is transiently expressed on activated T-cells. To determine whether blockade of the CD40-CD40L pathway can inhibit the production of anti-factor VIII antibodies, a clinical study has been designed in which patients with hemophilia A and a high titer inhibitor (> 10 BU) receive monthly exposures to factor VIII in the presence of a humanized mouse monoclonal antibody to human CD40L (hu5c8*). Subjects must be between the ages of 5 and 60 years old and be HIV seronegative. To date, three subjects have received at least three doses of hu5c8 at the initial protocol dose of 10 mg/kg. Preliminary results suggest that anti-CD40L inhibition may be effective in blocking anamnestic responses to factor VIII in some patients. It remains to be determined whether this effect will persist and whether patients may eventually become tolerant to factor VIII in the absence of hu5c8 co-administration.

    View details for PubMedID 11187868

  • Renal allograft protection with losartan in Fisher -> Lewis rats: Hemodynamics, macrophages, and cytokines KIDNEY INTERNATIONAL Ziai, F., Nagano, H., Kusaka, M., Coito, A. J., Troy, J. L., Nadeau, K. C., Rennke, H. G., Tilney, N. L., BRENNER, B. M., Mackenzie, H. S. 2000; 57 (6): 2618-2625

    Abstract

    We sought to assess the effects of angiotensin receptor blockade on glomerular hypertension, macrophage recruitment, and cytokine expression, all of which contribute to the development of chronic graft injury in this model.The effects of treatment with the specific angiotensin II type 1 (AT1) receptor antagonist, losartan, were assessed over 24 weeks in F344-->LEW rats (LOS, N = 9) versus vehicle-treated F344-->LEW controls (CON, N = 9).UprotV rose progressively in CON (from 7.0 +/- 2.9 to 41 +/- 17 mg/day at 24 wk) but remained at baseline in LOS (4.2 +/- 0.6 to 9.4 +/- 1.3 mg/day, P < 0.05 vs. CON). Glomerular capillary pressure (PGC) was increased in CON (71 +/- 1 mm Hg at week 20), but remained within the normal range in LOS rats (54 +/- 2 mm Hg, P < 0.05). Glomerulosclerosis averaged 0.3 +/- 0.2% in LOS versus 4 +/- 2% in CON rats (P < 0.05). Tubulointerstitial injury was minimal in both LOS and CON rats (+). The overexpression of renal cortical cytokine mRNA levels for the monocyte chemoattractants, monocyte chemoattractant protein-1 (MCP-1) and RANTES, as well as interleukin-1, inducible nitric oxide synthase, and transforming growth factor-beta, assessed by competitive reverse transcription-polymerase chain reaction, was suppressed in LOS versus CON rats at 20 weeks. Macrophage and T-cell numbers were decreased, and MCP-1, RANTES, and intercellular adhesion molecule-1 staining in the graft, identified by immunohistochemistry, were attenuated in LOS versus CON rats.The renoprotective effects of losartan in F344-->LEW rats were associated with lowered PGC, inhibition of macrophage chemoattractants and recruitment, and suppression of macrophage-associated cytokines at 20 weeks. These findings suggest that chronic allograft injury in F344-->LEW rats is, to a large extent, mediated by angiotensin II-dependent mechanisms and that these involve glomerular hemodynamics, macrophages, and macrophage-associated cytokines.

    View details for Web of Science ID 000087346100044

    View details for PubMedID 10844632

  • Cloning and characterization of the two enzymes responsible for trypanothione biosynthesis in Crithidia fasciculata JOURNAL OF BIOLOGICAL CHEMISTRY Tetaud, E., Manai, F., Barrett, M. P., Nadeau, K., Walsh, C. T., Fairlamb, A. H. 1998; 273 (31): 19383-19390

    Abstract

    Protozoa of the order Kinetoplastida differ from other organisms in their ability to conjugate glutathione (gamma-Glu-Cys-Gly) and spermidine to form trypanothione (N1,N8-bis(glutathionyl)spermidine), which is involved in maintaining intracellular thiol redox and in defense against oxidants. In this study, the genes from Crithidia fasciculata, Cf-GSS and Cf-TRS, which encode, respectively, glutathionylspermidine synthetase (EC 6.3.1.8) and trypanothione synthetase (EC 6.3.1.9) have been cloned and expressed. The deduced amino acid sequence of both Cf-GSS and Cf-TRS share 50% sequence similarity with the Escherichia coli glutathionylspermidine synthetase/amidase. Both genes are present as single copies in the C. fasciculata genome. When expressed in E. coli and Saccharomyces cerevisiae, neither protein was present in an active soluble form. However, thiol analysis of S. cerevisiae demonstrated that cells transformed with the Cf-GSS gene contained substantial amounts of glutathionylspermidine, whereas cells expressing both the Cf-GSS and Cf-TRS genes contained glutathionylspermidine and trypanothione, confirming that these genes encode the functional glutathionylspermidine and trypanothione synthetases from C. fasciculata. The translation products of Cf-GSS and Cf-TRS show significant homology to the amidase domain present in E. coli glutathionylspermidine synthetase, which can catalyze both synthesis and degradation of glutathionylspermidine. Glutathionylspermidine synthetase isolated from C. fasciculata was found to possess a similar amidase activity.

    View details for Web of Science ID 000075125200007

    View details for PubMedID 9677355

  • Effects of explosive brain death on cytokine activation of peripheral organs in the rat TRANSPLANTATION Takada, M., Nadeau, K. C., Hancock, W. W., Mackenzie, H. S., SHAW, G. D., Waaga, A. M., Chandraker, A., Sayegh, M. H., Tilney, N. L. 1998; 65 (12): 1533-1542

    Abstract

    The success rate of transplanted organs from brain-dead cadaver donors is consistently inferior to that of living sources. As cadaver and living unrelated donors are equally genetically disparate with a given recipient, the difference must lie within the donor himself and/or the effects of organ preservation and storage. We have hypothesized that irreversible central nervous system injury may up-regulate proinflammatory mediators and cell surface molecules in peripheral organs to be engrafted, making them more prone to host inflammatory and immunological responses.Rats undergoing surgically induced acutely increased intracranial pressure (explosive brain death) were followed for 6 hr. Their peripheral tissues were examined by reverse transcriptase polymerase chain reaction and immunohistology, serum factors were assessed by enzyme-linked immunosorbent assay, and the influence of inflammatory molecules in the blood stream was determined by cross-circulation experiments with normal animals.mRNA expression of both lymphocyte- and macrophage-associated products increased dramatically in all tissues. Similar factors in serum were coincidentally increased; these were shown to be active in vivo by cross-circulation with normal animals. The organs of all control groups, including animals with important ischemic injury and with hemorrhagic shock, were negative. Up-regulation of MHC class I and II antigens and the co-stimulatory molecule B7 suggests increased immunogenicity of the peripheral organs. These changes could be inhibited by: (i) administration of a recombinant soluble P-selectin glycoprotein ligand-Ig, a P- and E-selectin antagonist; and (ii) a fusion protein, cytotoxic T lymphocyte antigen 4-Ig, which blocks B7-mediated T-cell co-stimulation.Activation of peripheral organs following explosive brain death may be caused by various interrelated events, including the effects of massive acute central injury, hypotension, and circulating factors. Almost complete suppression of these changes could be produced by biological agents. Such interventions, if reproducible in humans, could improve the quality of organs from "marginal" donors, broadening the criteria for donor acceptance.

    View details for Web of Science ID 000074557600001

    View details for PubMedID 9665067

  • Late blockade of T cell costimulation interrupts progression of experimental chronic allograft rejection JOURNAL OF CLINICAL INVESTIGATION Chandraker, A., Azuma, H., Nadeau, K., Carpenter, C. B., Tilney, N. L., Hancock, W. W., Sayegh, M. H. 1998; 101 (11): 2309-2318

    Abstract

    Early blockade of T cell-costimulatory activation pathways prevents development of experimental chronic allograft rejection. Ongoing T cell recognition of alloantigen and activation may also play an important role in progression of chronic rejection, but definitive evidence is lacking. We used the fusion protein CTLA4Ig to block CD28-B7 T cell costimulation late after the onset of initial graft injury. Using the F334 into LEW rat model of chronic renal allograft rejection, transplant recipients were treated with a 10-d course of cyclosporine, and a subgroup received a single injection of CTLA4Ig at 8 wk after transplant. Functionally, CTLA4Ig administration prevented development of progressive proteinuria (14.3+/-4.1 mg/24 h versus 41.0+/-12.0 mg/24 h at 24 wk after transplant, P < 0.05). Histologically, graft mononuclear cell infiltration, glomerular hypertrophy, focal and segmental glomerulosclerosis, and intimal vascular hyperplasia were all attenuated in CTLA4Ig-treated animals. Lastly, reverse transcriptase-PCR and immunohistologic studies showed a significant reduction in the intragraft expression of key products of T cell and macrophage activation, and upregulation of what have recently been termed as "protective" genes, including the bcl family members, Bcl-2 and Bcl-xL, and hemoxygenase. Our data are the first to demonstrate that blocking T cell-costimulatory activation late after transplantation, after initial graft injury, prevents progression of chronic allograft rejection supporting the hypothesis that ongoing T cell recognition of alloantigen and activation are key mediators of ongoing chronic allograft rejection.

    View details for Web of Science ID 000074165900003

    View details for PubMedID 9616202

  • Influence of initial antigen-independent events on acute allograft rejection: Inhibition by a soluble P-selectin ligand and low-dose cyclosporine in combination International Congress on Immunosuppression Kusaka, M., Nadeau, K. C., Takada, M., Nagano, H., SHAW, G. D., Tilney, N. L. ELSEVIER SCIENCE INC. 1998: 1027–28

    View details for Web of Science ID 000074150800039

    View details for PubMedID 9636414

  • Infection-associated macrophage activation accelerates chronic renal allograft rejection in rats TRANSPLANTATION Nagano, H., Nadeau, K. C., Kusaka, M., Heeman, U. W., Tilney, N. L. 1997; 64 (11): 1602-1605

    Abstract

    The influence of infection-associated cellular activation on chronic rejection of kidney grafts was assessed in an established rat model by administration of lipopolysaccharide (LPS), an endotoxin and a potent stimulator of various cell populations including mononuclear cells and renal epithelial cells.Lewis recipients of F344 kidneys were treated with low-dose cyclosporine (1.5 mg/kg/day x 10 days). Animals with well-functioning grafts received a single dose of LPS (2 mg in 1 ml of NaCl, intraperitoneally) at 4 or 8 weeks after engraftment. Untreated control rats, which later experienced chronic rejection, were given 1 ml of NaCl.Administration of LPS during the early quiescent phase of chronic rejection accelerated the chronic process, functionally (proteinuria), morphologically, immunohistologically, and by reverse-transcriptase polymerase chain reaction as compared with untreated controls. Infiltration of macrophages and their associated factors was especially affected.As the later events of chronic rejection seem to be mediated primarily by macrophages and their products, administration of LPS accelerated the tempo and activity of these cells in the development of chronic rejection. These findings may explain the clinical observation that infection may be an important risk factor for chronic allograft rejection.

    View details for Web of Science ID 000071034100018

    View details for PubMedID 9415565

  • Prevention of late renal changes after initial ischemia/reperfusion injury by blocking early selectin binding TRANSPLANTATION Takada, M., Nadeau, K. C., SHAW, G. D., Tilney, N. L. 1997; 64 (11): 1520-1525

    Abstract

    Increasing clinical evidence suggests that delayed initial function secondary to ischemia/reperfusion injury alone, and particularly in combination with early episodes of acute rejection, reduces kidney allograft survival over time.We investigated changes developing over the long term following a standardized ischemia/reperfusion insult in a Lewis rat model. The left kidney was isolated in a uninephrectomized host and cooled, and the pedicle was clamped for 45 min. Animals were followed for 48 weeks after initial renal injury. Organs were removed serially (4, 8, 16, 24, 32, 40, and 48 weeks) for immunohistology and reverse transcriptase polymerase chain reaction.Progressive proteinuria developed after 8 weeks. By immunohistology, CD4+ leukocytes and ED-1+ macrophages infiltrated the ischemic organs in parallel with up-regulation of major histocompatibility complex class II antigen expression. Because macrophages have been shown to be critical in chronic changes in other models, they were examined primarily in these studies. By reverse transcriptase polymerase chain reaction, macrophage-derived, fibrosis-inducing factors (transforming growth factor-beta, interleukin 6, and tumor necrosis factor-alpha) remained highly and constantly expressed throughout the follow-up period. The long-term influence of initial treatment with the soluble form of P-selectin glycoprotein ligand-1, a soluble ligand for P- and E-selectin, was then examined. All functional and structural changes remained at relative baseline, similar to uninephrectomized controls.These data suggest that blocking the initial selectin-mediated step after ischemia/reperfusion injury, which triggers significant early cellular and molecular events, also reduces later renal dysfunction and tissue damage over time. In part, the findings may be explained by the sparing of functioning nephron units, which if destroyed or compromised by the original insult, may contribute to long-term graft failure. This approach may be important clinically in the transplantation of kidneys from non-heart-beating or marginal donors or organs experiencing prolonged ischemic times.

    View details for Web of Science ID 000071034100003

    View details for PubMedID 9415550

  • CD28-B7 blockade in organ dysfunction secondary to cold ischemia/reperfusion injury - Rapid Communication KIDNEY INTERNATIONAL Chandraker, A., Takada, M., Nadeau, K. C., Peach, R., Tilney, N. L., Sayegh, M. H. 1997; 52 (6): 1678-1684

    Abstract

    Ischemic injury to cadaver organs is a major risk factor for development of chronic organ dysfunction. We have recently shown that the B7 costimulatory pathway plays a critical role in early organ dysfunction developing after renal cold ischemia/reperfusion injury. We extended these observations to investigate the role of this pathway in the development and progression of chronic organ dysfunction following such injury. Uninephrectomized rats which underwent cold ischemia/reperfusion injury developed progressive proteinuria as compared to uninephrectomized controls. Animals treated with CTLA4Ig, which blocks B7 costimulation, starting on the day of injury had significantly better long-term survival and developed significantly less proteinuria than control animals treated with control Ig. RT-PCR analysis of kidney tissue showed significant reduction in expression of activation and inflammatory cytokines, chemoattractants, and growth factors, as compared to controls. Delaying administration of CTLA4Ig for one week, but not four weeks, after injury was still effective in ameliorating development of progressive proteinuria. Interestingly, selective blockade of B7-1 by a mutant form of CTLA4Ig had no effect on early or chronic organ dysfunction. These findings indicate the long-term functional and molecular consequences of experimental cold ischemia/reperfusion injury, and suggest that B7-2 is critical in the development of organ dysfunction following ischemic injury, even in the absence of alloantigen.

    View details for Web of Science ID A1997YH57300028

    View details for PubMedID 9407517

  • The role of the B7 costimulatory pathway in experimental cold ischemia/reperfusion injury JOURNAL OF CLINICAL INVESTIGATION Takada, M., Chandraker, A., Nadeau, K. C., Sayegh, M. H., Tilney, N. L. 1997; 100 (5): 1199-1203

    Abstract

    Ischemia/reperfusion injury associated with organ retrieval and storage influences the development of chronic graft dysfunction, the major clinical problem in solid organ transplantation. The potential role of mononuclear cells (T cells and monocyte/macrophages) in this type of injury is unknown. Inbred male Lewis rats were uninephrectomized and the left kidney perfused in situ with 10 ml of iced University of Wisconsin solution. Immunohistological studies showed mononuclear cell infiltration of the ischemic organs associated with the upregulation of MHC class II antigen expression. Reverse transcriptase-PCR indicated that T cell associated cytokines and monocyte/macrophage activation markers/products are upregulated early after the ischemic insult. B7 expression occurred within 24 h and peaked at 3 d. Plasma creatinine levels rose transiently with complete recovery of renal function by 5 d. Animals began to develop progressive proteinuria after 8-12 wk, indicative of the long-term functional consequences of early ischemia/reperfusion injury. Blockade of T cell CD28-B7 costimulation with CTLA4Ig resulted in significant inhibition of T cell and macrophage infiltration and activation in situ. Treated animals did not exhibit transient renal dysfunction, nor developed proteinuria over time. This is the first demonstration that blocking T cell costimulatory activation in the absence of alloantigen can prevent the early and late consequences of ischemia/reperfusion injury.

    View details for Web of Science ID A1997XV75300029

    View details for PubMedID 9276737

  • Cellular and molecular predictors of chronic renal dysfunction after initial ischemia/reperfusion injury of a single kidney TRANSPLANTATION Azuma, H., Nadeau, K., Takada, M., Mackenzie, H. S., Tilney, N. L. 1997; 64 (2): 190-197

    Abstract

    Initial ischemia/reperfusion injury occurring secondary to organ retrieval, storage, and transplantation has been associated with late renal allograft deterioration and failure. In addition, there is an apparent synergy, reported in several clinical series, between the initial injuries of ischemia/reperfusion and acute rejection; the long-term results of graft survival are significantly deceased after both events in combination as compared with either alone or if no such episodes occur.In the present study, we examined patterns of proteinuria, cellular infiltration, cytokine expression, and glomerulosclerosis over time in Lewis and Fischer 344 rats after 45 min of warm ischemia of a single kidney and with or without contralateral nephrectomy. Both early (4 hr to 7 days) and late (2-52 weeks) events were studied serially in the affected kidneys morphologically, by immunohistology and by reverse transcriptase polymerase chain reaction.Intercellular adhesion molecule 1, endothelin, and major histocompatibility complex class II expression were up-regulated within 2 to 5 days after injury; T cells and macrophages increased transiently. Proteinuria developed after approximately 8 weeks only in animals bearing a single injured kidney, and not in those with a retained native organ. Progressive morphological changes occurred after 16 weeks, including glomerulosclerosis, arterial obliteration, and interstitial fibrosis. After a period of relative quiescence, expression of intercellular adhesion molecule 1 again increased in relation to progressive macrophage infiltration and their associated products, particularly, interleukin 1, tumor necrosis factor-alpha, transforming growth factor-beta, and inducible nitric oxide synthase. Monocyte chemotactic protein 1 was intensely up-regulated by 24 weeks, coincident with a dramatic rise in this infiltrating population. These changes remained virtually at baseline in animals with a retained native kidney.These data imply that chronic injury after significant initial ischemia and reperfusion occurs when there is already a 50% renal mass reduction, but not when two kidneys remain in place. Permanent nephron loss resulting from such an insult could account for this phenomenon. Early ischemia and reperfusion, if severe enough in a single kidney, may be an important antigen-independent risk factor for later renal deterioration and failure. In the context of a renal allograft, it may contribute to chronic rejection.

    View details for Web of Science ID A1997XN86900002

    View details for PubMedID 9256172

  • The cytokine-adhesion molecule cascade in ischemia/reperfusion injury of the rat kidney - Inhibition by a soluble P-selectin ligand JOURNAL OF CLINICAL INVESTIGATION Takada, M., Nadeau, K. C., SHAW, G. D., MARQUETTE, K. A., Tilney, N. L. 1997; 99 (11): 2682-2690

    Abstract

    Ischemia/reperfusion (I/R) injury associated with renal transplantation may influence both early graft function and late changes. The initial (

    View details for Web of Science ID A1997XD35700018

    View details for PubMedID 9169498

  • Sequential cellular and molecular kinetics in acutely rejecting renal allografts in rats TRANSPLANTATION Nagano, H., Nadeau, K. C., Takada, M., Kusaka, M., Tilney, N. L. 1997; 63 (8): 1101-1108

    Abstract

    The initial (0-24 hr), early (3-5 days), and late (7-14 days) events occurring in LBNF1 renal allografts transplanted into Lew recipients were examined to define precisely the sequential cellular and molecular kinetics during acute rejection. Grafts and spleens were harvested at 3, 6, 12, and 24 hr, and at 3, 5, 7, and 14 days and processed for morphology, immunohistology, and reverse transcriptase-polymerase chain reaction. Various factors (mRNA) were up-regulated sequentially in the allografts over time. In the initial phase, E-selectin and complement (C1 and C3) expression was noted within 6 hr, peaking by 24 hr. RANTES (regulated upon activation, normal T cell expressed and secreted) increased within 6 hr, and then again between 3 and 6 days. By immunohistology, MHC class II was up-regulated consistently after day 1. Intercellular adhesion molecule-1 expression increased after day 3; lymphocyte function-associated antigen-1+ infiltrating leukocytes peaked at day 5. Infiltrating CD8+ T lymphocytes increased strikingly between days 1 and 3, peaking at day 5; CD4+ cells infiltrated more slowly until day 5. The kinetics of ED1+ macrophages were similar to those of lymphocyte function-associated antigen-1+ cells. The CD4+ T cell-derived product, interleukin (IL)-2, peaked at 7 days. Interferon-gamma increased progressively up to 14 days. By 3 days, the macrophage-associated factor, transforming growth factor-beta, peaked; this was followed by increased IL-6 expression by day 5. IL-1, tumor necrosis factor-alpha, and inducible nitric oxide synthase increased slowly until day 7, declining thereafter. Endothelin increased progressively over the 14-day follow-up period. Cytokine dynamics occurring in host spleen were similar to those noted in the allografts. Although acute rejection is primarily T cell mediated, adhesion molecules, macrophages, and their associated products may influence initial and later changes. The brisk expression of complement, E-selectin, and RANTES within the first few hours after engraftment may occur secondary to ischemic injury and trigger subsequent immunological events. Macrophages and their products may play a larger role in the process than hitherto appreciated.

    View details for Web of Science ID A1997WW66000009

    View details for PubMedID 9133471

  • Unaccompanied children in detention in the US PEDIATRICS Nadeau, K. C. 1997; 99 (4): 653-653

    View details for Web of Science ID A1997WQ80200052

    View details for PubMedID 9093327

  • Immigrating unaccompanied miners - A neglected minority? WESTERN JOURNAL OF MEDICINE Nadeau, K., Hannibal, K., Sirkin, S., Nightingale, E. O. 1997; 166 (3): 221-221

    View details for Web of Science ID A1997WW66700014

    View details for PubMedID 9143205

  • Nephron mass modulates the hemodynamic, cellular, and molecular response of the rat renal allograft TRANSPLANTATION Azuma, H., Nadeau, K., Mackenzie, H. S., BRENNER, B. M., Tilney, N. L. 1997; 63 (4): 519-528

    Abstract

    Functioning nephron mass has recently been implicated as a risk factor for development of chronic "rejection" of kidney allografts. Reductions in nephron number below 50% may induce glomerular hypertension and hyperfiltration in surviving units, which in turn lead to graft injury. In the present study, which extends and amplifies our previous investigations, cellular and molecular characteristics of single allografts from F344 donors in bilaterally nephrectomized LEW recipients, our standard experimental model of chronic renal allograft dysfunction, were compared with allografts from recipients where total renal mass was reduced (by ligating branches of the graft renal artery) or restored to normal levels by transplanting or retaining a second kidney. Our findings in this study confirm that progressive proteinuria and structural injury in recipients of single allografts were accentuated in grafts with reduced mass but virtually absent in rats with increased kidney mass. A striking observation was that patterns of cell surface molecule expression, cellular infiltration, and expression of all T cell- and macrophage-associated products studied were all markedly modulated by changes in renal mass. Moreover, several molecules that are up-regulated before evidence of graft injury are down-regulated by providing increased renal mass. These data show that the quantity of functioning renal mass is not only an important independent determinant of the tempo and intensity of chronic renal allograft failure, but also a potent modulator of fundamental cellular and molecular components of a complex process. This phenomenon involves antigen-dependent and antigen-independent elements that ultimately result in chronic allograft failure.

    View details for Web of Science ID A1997WL85500006

    View details for PubMedID 9047144

  • Inhibition of CD28-B7 T-cell costimulatory activation pathway affects intragraft cytokine and growth factor expression in chronic renal allograft rejection XVI International Congress of the Transplantation-Society Nadeau, K., Azuma, H., Chandraker, A., Sayegh, M. H., Tilney, N. L. ELSEVIER SCIENCE INC. 1997: 1038–38

    View details for Web of Science ID A1997WM12700453

    View details for PubMedID 9123187

  • Initial ischemia/reperfusion injury influences late functional and structural changes in the kidney XVI International Congress of the Transplantation-Society Azuma, H., Nadeau, K., Takada, M., Tilney, N. L. ELSEVIER SCIENCE INC. 1997: 1528–29

    View details for Web of Science ID A1997WM12700678

    View details for PubMedID 9123412

  • Early cellular and molecular changes in ischemia/reperfusion injury: Inhibition by a selectin antagonist, P-selectin glycoprotein ligand-1 XVI International Congress of the Transplantation-Society Takada, M., Nadeau, K. C., SHAW, G. D., Tilney, N. L. ELSEVIER SCIENCE INC. 1997: 1324–25

    View details for Web of Science ID A1997WM12700591

    View details for PubMedID 9123325

  • Sequential cytokine expression in renal allografts in rats immunosuppressed with maintenance cyclosporine or mycophenolate mofetil TRANSPLANTATION Nadeau, K. C., Azuma, H., Tilney, N. L. 1996; 62 (9): 1363-1366

    Abstract

    Although the immunosuppressive agents used clinically modulate acute rejection of organ allografts, their ability to prevent chronic rejection has been less clear. To ascertain the effects of prolonged maintenance treatment with cyclosporine (CsA) and mycophenolate mofetil, we examined sequential patterns of cytokine regulation by reverse transcriptase polymerase chain reaction in long-surviving renal allografts in treated recipients. In renal allografts in animals on long-term CsA therapy, there is important up-regulation of transforming growth factor-beta, Hsp70, and endothelin as compared with control animals. Conversely, interleukin-2 receptor, interferon-gamma, and tumor necrosis factor-alpha in kidney grafts in this group were expressed at lower levels compared with those noted in chronically rejecting grafts in control animals that had received only CsA for 10 days after transplantation. Morphologically, the long-term CsA-treated kidneys had more extensive arterial obliterative changes and glomerulosclerosis after 24 weeks than control organs; these changes can presumably be attributed to the nephrotoxic effects of this drug combined with the progressive changes of chronic rejection. In contrast, mycophenolate mofetil inhibited the production of all lymphocyte and macrophage-derived cytokines throughout the entire follow-up period. Allograft kidneys in these latter recipients showed no late morphological abnormalities. This agent may be important clinically in preventing chronic rejection.

    View details for Web of Science ID A1996VU11700034

    View details for PubMedID 8932288

  • Blockade of T-cell costimulation prevents development of experimental chronic renal allograft rejection PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Azuma, H., Chandraker, A., Nadeau, K., Hancock, W. W., Carpenter, C. B., Tilney, N. L., Sayegh, M. H. 1996; 93 (22): 12439-12444

    Abstract

    Blocking CD28-B7 T-cell costimulation by systemic administration of CTLA4Ig, a fusion protein which binds B7 molecules on the surface of antigen-presenting cells, prevents rejection and induces tolerance in experimental acute allograft rejection models. We tested the effect of CTLA4Ig therapy on the process of chronic renal allograft rejection using an established experimental transplantation model. F344 kidneys were transplanted orthotopically into bilaterally nephrectomized LEW recipients. Control animals received low dose cyclosporine for 10 days posttransplantation. Administration of a single injection of CTLA4Ig on day 2 posttransplant alone or in addition to the low dose cyclosporine protocol resulted in improvement of long-term graft survival as compared with controls. More importantly, control recipients which received cyclosporine only developed progressive proteinuria by 8-12 weeks, and morphological evidence of chronic rejection by 16-24 weeks, including widespread transplant arteriosclerosis and focal and segmental glomerulosclerosis, while animals treated with CTLA4Ig alone or in addition to cyclosporine did not. Competitive reverse transcriptase-PCR and immunohistological analysis of allografts at 8, 16, and 24 weeks showed attenuation of lymphocyte and macrophage infiltration and activation in the CTLA4Ig-treated animals, as compared with cyclosporine-alone treated controls. These data confirm that early blockade of the CD28-B7 T-cell costimulatory pathway prevents later development and evolution of chronic renal allograft rejection. Our results indicate that T-cell recognition of alloantigen is a central event in initiating the process of chronic rejection, and that strategies targeted at blocking T-cell costimulation may prove to be a valuable clinical approach to preventing development of the process.

    View details for Web of Science ID A1996VP93700071

    View details for PubMedID 8901600

  • Inflammatory mediators, cells and their products in acute host alloresponsiveness. Annals of transplantation Tilney, N. L., Nadeau, K. 1996; 1 (3): 5-13

    View details for PubMedID 9869913

  • Prevention of functional, structural, and molecular changes of chronic rejection of rat renal allografts by a specific macrophage inhibitor 14th Annual Meeting of the American-Society-of-Transplant-Physicians Azuma, H., Nadeau, K. C., Ishibashi, M., Tilney, N. L. WILLIAMS & WILKINS. 1995: 1577–82

    Abstract

    Chronic rejection is the primary cause of long-term allograft loss. Macrophages and their products have been shown to be critical in the development of this process in an established kidney allograft rat model. A new synthetic agent, Gamma lactone, is a specific inhibitor of macrophages and monocytes that inhibits the generation of these populations in vitro and their activities in the effector phase of host alloresponsiveness. We tested its effects on the development of chronic changes in the model. Untreated control allograft recipients developed increasing proteinuria after 12 weeks; progressive glomerulosclerosis, interstitial fibrosis, and arterial obliteration developed thereafter. Infiltrating ED1+ macrophages as noted by immunohistology increased dramatically between 12 and 16 weeks, localizing preferentially in glomeruli and perivascular areas. The presence of these cells was associated with dense expression of their products. Reverse transcription polymerase chain reaction confirmed and expanded the immunohistological findings, showing significant gene expression of macrophage-derived mediators. In contrast, recipients treated with G-Lac daily for 32 weeks never developed proteinuria; macrophage infiltration was dramatically reduced, and expression of their products was virtually absent. At 32 weeks, most glomeruli and arteries remained histologically normal. In another group in which treatment was stopped at 24 weeks, however, proteinuria began to develop by 32 weeks; macrophages infiltrated the organs and expression of their products became manifest. These results confirm the importance of macrophages and macrophage-derived factors in chronic rejection and suggest that a specific inhibitor of macrophage activation may be useful in the prevention of the process over the long term.

    View details for Web of Science ID A1995TN23000034

    View details for PubMedID 8545893

  • SEQUENTIAL CYTOKINE DYNAMICS IN CHRONIC REJECTION OF RAT RENAL-ALLOGRAFTS - ROLES FOR CYTOKINES RANTES AND MCP-1 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Nadeau, K. C., Azuma, H., Tilney, N. L. 1995; 92 (19): 8729-8733

    Abstract

    Chronic rejection, the most important cause of long-term graft failure, is thought to result from both alloantigen-dependent and -independent factors. To examine these influences, cytokine dynamics were assessed by semiquantitative competitive reverse transcriptase-PCR and by immunohistology in an established rat model of chronic rejection lf renal allografts. Isograft controls develop morphologic and immunohistologic changes that are similar to renal allograft changes, although quantitatively less intense and at a delayed speed; these are thought to occur secondary to antigen-independent events. Sequential cytokine expression was determined throughout the process. During an early reversible allograft rejection episode, both T-cell associated [interleukin (IL) 2, IL-2 receptor, IL-4, and interferon gamma] and macrophage (IL-1 alpha, tumor necrosis factor alpha, and IL-6) products were up-regulated despite transient immunosuppression. RANTES (regulated upon activation, normal T-cell expressed and secreted) peaked at 2 weeks; intercellular adhesion molecule (ICAM-1) was maximally expressed at 6 weeks. Macrophage products such as monocyte chemoattractant protein (MCP-1) increased dramatically (to 10 times), presaging intense peak macrophage infiltration at 16 weeks. In contrast, in isografts, ICAM-1 peaked at 24 weeks. MCP-1 was maximally expressed at 52 weeks, commensurate with a progressive increase in infiltrating macrophages. Cytokine expression in the spleen of allograft and isograft recipients was insignificant. We conclude that chronic rejection of kidney allografts in rats is predominantly a local macrophage-dependent event with intense up-regulation of macrophage products such as MCP-1, IL-6, and inducible nitric oxide synthase. The cytokine expression in isografts emphasizes the contribution of antigen-independent events. The dynamics of RANTES expression between early and late phases of chronic rejection suggest a key role in mediating the events of the chronic process.

    View details for Web of Science ID A1995RU75900040

    View details for PubMedID 7568006

  • QUANTITATION OF THE INTERACTION OF THE IMMUNOSUPPRESSANT DEOXYSPERGUALIN AND ANALOGS WITH HSC70 AND HSP90 BIOCHEMISTRY Nadeau, K., Nadler, S. G., Saulnier, M., Tepper, M. A., Walsh, C. T. 1994; 33 (9): 2561-2567

    Abstract

    Deoxyspergualin (DSG), a spermidinyl, alpha-hydroxyglycyl, 7-guanidinoheptanoyl peptidomimetic, shows immunosuppressive activity. In confirmation of a recent report that immobilized methoxyDSG selectively retains the heat shock protein Hsc70, we report here quantitative binding of DSG and analogs to both Hsc70 and the 90-kDa heat shock protein Hsp90. We have utilized affinity capillary electrophoresis to obtain Kd values for DSG and analogs, and stimulation of the ATPase activity of Hsc70 to obtain Km values for DSG, that are comparable and corroborative. Kd values are 4 microM for DSG binding to Hsc70 and 5 microM for DSG binding to Hsp90. Two active analogs, methoxy- and glycylDSG, bind with similar affinities. Glyoxylylspermidine and des(aminopropyl)DSG, two inactive metabolites, have much reduced affinity for Hsc70 and Hsp90. These data validate binding of these novel immunosuppressant agents to these molecular chaperones, at concentrations in the range of pharmacologically active doses, and indicate that further characterization of Hsc70 and/or Hsp90 as potential targets for DSG is warranted.

    View details for Web of Science ID A1994MZ69700027

    View details for PubMedID 8117717

  • MOLECULAR AND BIOCHEMICAL-COMPARISON OF THE 70-KDA HEAT-SHOCK PROTEINS OF TRYPANOSOMA-CRUZI JOURNAL OF BIOLOGICAL CHEMISTRY Olson, C. L., Nadeau, K. C., Sullivan, M. A., Winquist, A. G., Donelson, J. E., Walsh, C. T., Engman, D. M. 1994; 269 (5): 3868-3874

    Abstract

    An analysis of the genetic organization, regulated expression and biochemical properties of the cytoplasmic/nuclear (hsp70) and mitochondrial (mtp70) 70-kDa heat shock proteins of Trypanosoma cruzi is presented. The two proteins are encoded by tandemly arranged gene families that are located on different chromosomes. Both are mildly heat-inducible but have different optimal temperatures for expression. During the switch from proliferation to differentiation that occurs during the growth of T. cruzi in culture, the hsp70 level decreases dramatically while the mtp70 level falls only slightly. The subcellular locations of the two proteins differ during heat shock. While mtp70 remains associated with the kinetoplast at all temperatures, hsp70 becomes more concentrated in the nucleus at higher temperatures. Biochemical analysis of hsp70 and mtp70 revealed both to be potent ATPases. Each protein binds ATP with a Km of about 70 microM and hydrolyzes ATP with a kcat of about 100 min-1, 100 times greater than the kcat of human hsp70. The high ATPase activities of hsp70 and mtp70 are further stimulated by incubation with peptides, suggesting that these trypanosome heat shock proteins have protein chaperone activity. Finally, mtp70, but not hsp70, was found to possess autophosphorylation activity in vitro, a property that it shares with prokaryotic hsp70. These findings demonstrate unique cellular and biochemical characteristics of T. cruzi mtp70 and hsp70 that suggest that they play distinct physiologic roles in the biology of the cell.

    View details for Web of Science ID A1994MV63100107

    View details for PubMedID 8106432

  • HSP90 CHAPERONINS POSSESS ATPASE ACTIVITY AND BIND HEAT-SHOCK TRANSCRIPTION FACTORS AND PEPTIDYL PROLYL ISOMERASES JOURNAL OF BIOLOGICAL CHEMISTRY Nadeau, K., Das, A., Walsh, C. T. 1993; 268 (2): 1479-1487

    Abstract

    Heat shock proteins of the 82-90 kDa class (hsp82 and hsp90) are abundant, conserved, and ubiquitous from prokaryotes to eukaryotes. Although proposed to be chaperones, they had not been reported to possess enzymatic activity until our recent observation that pure trypanosomatid hsp83 had potent ATPase activity (Nadeau, K., Sullivan, M., Engman, D., and Walsh, C. T. (1992) Protein Sci. 1, 970-979). We have now purified the hsp90 homolog from Escherichia coli (HtpG) and from Saccharomyces cerevisiae (hsp82) to homogeneity and observe ATPase activity with kcat values of 3 min-1 and 140 min-1. In addition, examinations of purified rat hsp90 and human hsp90 detect ATPase activity with a kcat of 0.6 min-1 and 10 min-1. Each of these hsp90s undergoes autophosphorylation on serine or threonine residues. In prokaryotes and eukaryotes, the induction of hsps during heat shock is controlled, respectively, by the binding of an alternate sigma 32 or a transcriptional activator (heat shock factor or HSF) at heat shock promoter elements. Here we show that E. coli HtpG immobilized to Affi-Gel beads selectively retains sigma 32 while the yeast hsp90 and rat hsp90 retain HSF. The peptidyl prolyl isomerase hsp59 of the FK506 binding class is known to bind to hsp90. We also detect binding of the other family of PPIases, the cyclophilins, to immobilized hsp90, consistent with a functional convergence of protein foldases.

    View details for Web of Science ID A1993KG07700106

    View details for PubMedID 8419347

  • STUDIES ON THE INTERACTION OF THE IMMUNOSUPPRESSANT 15-DEOXYSPERGUALIN WITH HEAT-SHOCK PROTEINS Conference on Immunosuppressive and Antiinflammatory Drugs Nadler, S. G., Cleaveland, J., Tepper, M. A., Walsh, C., Nadeau, K. NEW YORK ACAD SCIENCES. 1993: 412–414

    View details for Web of Science ID A1993BZ60M00047

    View details for PubMedID 8109853

  • 83-KILODALTON HEAT-SHOCK PROTEINS OF TRYPANOSOMES ARE POTENT PEPTIDE-STIMULATED ATPASES PROTEIN SCIENCE Nadeau, K., Sullivan, M. A., Bradley, M., Engman, D. M., Walsh, C. T. 1992; 1 (8): 970-979

    Abstract

    A Crithidia fasciculata 83-kDa protein purified during a separate study of C. fasciculata trypanothione synthetase was shown to have ATPase activity and to belong to the hsp90 family of stress proteins. Because no ATPase activity has previously been reported for the hsp90 class, ATP utilization by C. fasciculata hsp83 was characterized: this hsp83 has an ATPase kcat of 150 min-1 and a Km of 60 microM, whereas the homologous mammalian hsp90 binds ATP but has no ATPase activity. Crithidia fasciculata hsp83 undergoes autophosphorylation on serine and threonine at a rate constant of 3.3 x 10(-3) min-1. Similar analysis was performed on recombinant Trypanosoma cruzi hsp83, and comparable ATPase parameters were obtained (kcat = 100 min-1, Km = 80 microM, kautophosphorylation = 6.3 x 10(-3) min-1). The phosphoenzyme is neither on the ATPase hydrolytic pathway nor does it affect ATPase catalytic efficiency. Both C. fasciculata and T. cruzi hsp83 show up to fivefold stimulation of ATPase activity by peptides of 6-24 amino acids.

    View details for Web of Science ID A1992JM67800002

    View details for PubMedID 1304385

  • KINETIC ISOTOPE EFFECT ANALYSIS OF THE REACTION CATALYZED BY TRYPANOSOMA-CONGOLENSE TRYPANOTHIONE REDUCTASE BIOCHEMISTRY LEICHUS, B. N., Bradley, M., Nadeau, K., Walsh, C. T., Blanchard, J. S. 1992; 31 (28): 6414-6420

    Abstract

    African trypanosomes are devoid of glutathione reductase activity, and instead contain a unique flavoprotein variant, trypanothione reductase, which acts on a cyclic derivative of glutathione, trypanothione. The high degree of sequence similarity between trypanothione reductase and glutathione reductase, as well as the obvious similarity in the reactions catalyzed, led us to investigate the pH dependence of the kinetic parameters, and the isotopic behavior of trypanothione reductase. The pH dependence of the kinetic parameters V, V/K for NADH, and V/K for oxidized trypanothione has been determined for trypanothione reductase from Trypanosoma congolense. Both V/K for NADH and the maximum velocity decrease as single groups exhibiting pK values of 8.87 +/- 0.09 and 9.45 +/- 0.07, respectively, are deprotonated. V/K for oxidized trypanothione, T(S)2, decreases as two groups exhibiting experimentally indistinguishable pK values of 8.74 +/- 0.03 are deprotonated. Variable magnitudes of the primary deuterium kinetic isotope effects on pyridine nucleotide oxidation are observed on V and V/K when different pyridine nucleotide substrates are used, and the magnitude of DV and D(V/K) is independent of the oxidized trypanothione concentration at pH 7.25. Solvent kinetic isotope effects, obtained with 2',3'-cNADPH as the variable substrate, were observed on V only, and plots of V versus mole fraction of D2O (i.e., proton inventory) were linear, and yielded values of 1.3-1.6 for D2OV. Solvent kinetic isotope effects obtained with alternate pyridine nucleotides as substrates were also observed on V, and the magnitude of D2OV decreases for each pyridine nucleotide as its maximal velocity relative to that of NADPH oxidation decreases.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1992JE53600008

    View details for PubMedID 1633154

  • PURIFICATION OF GLUTATHIONYLSPERMIDINE AND TRYPANOTHIONE SYNTHETASES FROM CRITHIDIA-FASCICULATA PROTEIN SCIENCE Smith, K., Nadeau, K., Bradley, M., Walsh, C., Fairlamb, A. H. 1992; 1 (7): 874-883

    Abstract

    Two enzymes involved in the biosynthesis of the trypanosomatid-specific dithiol trypanothione-glutathionylspermidine (Gsp) synthetase and trypanothione (TSH) synthetase--have been identified and purified individually from Crithidia fasciculata. The Gsp synthetase has been purified 93-fold and the TSH synthetase 52-fold to apparent homogeneity from a single DEAE fraction that contained both activities. This constitutes the first indication that the enzymatic conversion of two glutathione molecules and one spermidine to the N1,N8-bis(glutathionyl)spermidine (TSH) occurs in two discrete enzymatic steps. Gsp synthetase, which has a kcat of 600/min, shows no detectable TSH synthetase activity, whereas TSH synthetase does not make any detectable Gsp and has a kcat of 75/min. The 90-kDa Gsp synthetase and 82-kDa TSH synthetase are separable on phenyl Superose and remain separated on gel filtration columns in high salt (0.8 M NaCl). Active complexes can be formed under low to moderate salt conditions (0.0-0.15 M NaCl), consistent with a functional complex in vivo.

    View details for Web of Science ID A1992JF88300005

    View details for PubMedID 1304372

  • MOLECULAR STUDIES ON TRYPANOTHIONE REDUCTASE - AN ANTIPARASITIC TARGET ENZYME CURRENT TOPICS IN CELLULAR REGULATION Walsh, C., Bradley, M., Nadeau, K. 1992; 33: 409-417

    View details for Web of Science ID A1992MD69600023

    View details for PubMedID 1354149

  • MOLECULAR STUDIES ON TRYPANOTHIONE REDUCTASE, A TARGET FOR ANTIPARASITIC DRUGS TRENDS IN BIOCHEMICAL SCIENCES Walsh, C., Bradley, M., Nadeau, K. 1991; 16 (8): 305-309

    Abstract

    Trypanosoma and Leishmania are parasitic protozoa that cause a variety of diseases, which include African sleeping sickness and oriental sore. Attempts to determine pharmaceutically exploitable differences between host and parasite biochemistry have identified the unique trypanothione pathway as a possible target. This pathway includes the enzyme trypanothione reductase, the parasite analogue of glutathione reductase.

    View details for Web of Science ID A1991GA13000013

    View details for PubMedID 1957352

  • A TEST FOR GENETIC EXCHANGE IN MIXED INFECTIONS OF LEISHMANIA-MAJOR IN THE SAND FLY PHLEBOTOMUS-PAPATASI JOURNAL OF PROTOZOOLOGY PANTON, L. J., Tesh, R. B., Nadeau, K. C., Beverley, S. M. 1991; 38 (3): 224-228

    Abstract

    We tested if genetic exchange was observable between two strains of Leishmania major (Trypanosomatidae) during mixed infection of the sand fly Phlebotomus papatasi. Previous studies suggested that genetic exchange may occur in natural populations of Leishmania at a low frequency, but experimental crosses examining small numbers of progeny (less than 60) did not reveal hybrid parasites. Accordingly, a strategy was devised to increase the number of progeny that could be screened by 100-fold. Clonal derivatives from two strains that were infective to flies and contained numerous restriction fragment length polymorphisms were characterized and selected for resistance to methotrexate or tunicamycin by gene amplification. A successfully mixed infection of P. papatasi was obtained, and a method was developed for directly plating promastigotes from the gut contents of infected flies onto selective media. Twenty-five hundred independent progeny were scored for the presence of both drug resistance markers. No hybrid parasites were observed, indicating that the frequency of genetic exchange in this cross must be less than 4 x 10(-4). The lines and methods established in this work may prove useful in future studies of the mechanism and frequency of gene exchange in Leishmania.

    View details for Web of Science ID A1991FQ06400010

    View details for PubMedID 1880760

  • THE PROMOTER OF THE LATENCY-ASSOCIATED TRANSCRIPTS OF HERPES-SIMPLEX VIRUS TYPE-1 CONTAINS A FUNCTIONAL CAMP-RESPONSE ELEMENT - ROLE OF THE LATENCY-ASSOCIATED TRANSCRIPTS AND CAMP IN REACTIVATION OF VIRAL LATENCY PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Leib, D. A., Nadeau, K. C., Rundle, S. A., Schaffer, P. A. 1991; 88 (1): 48-52

    Abstract

    A 203-base-pair sequence 5' of the latency-associated transcripts (LATs) of herpes simplex virus type 1 contains a 7-base consensus sequence TGCGTCA that is identical to the cAMP-response element of the proenkephalin gene. This consensus sequence is at -38 relative to the putative 5' end of the LATs with a TATA box at the -24 position. In transient chloramphenicol acetyltransferase assays in rat pheochromocytoma (PC12) cells, this enhancer region stimulated gene expression up to 3-fold in the presence of dibutyryl cAMP, forskolin, nerve growth factor, or phorbol 12-myristate 13-acetate. Mutation of the cAMP-response element to TGCG-CAA resulted in a 4-fold reduction of basal activity and a complete loss of inducible stimulation. In DNA gel retardation assays, purified cAMP-response element-binding protein and a nuclear protein from PC12 cells were shown to bind specifically to this element. Furthermore, it was demonstrated that the reactivation of wild-type herpes simplex virus type 1 from dissociated latently infected murine trigeminal ganglia was significantly accelerated (P less than 0.005) by the addition of cAMP analogs or adenylate cyclase activators. However, these reagents did not accelerate reactivation of a deletion mutant that lacks the putative cAMP-response element-containing promoter region, transcriptional start site, and 1015 base pairs of the LATs. These studies demonstrate that the promoter region of the LATs contains a functional cAMP-response element and that expression of the LATs is likely controlled by second messenger signal transduction and imply a role for cAMP in triggering viral reactivation.

    View details for Web of Science ID A1991EQ54400011

    View details for PubMedID 1846042