Bio


Dr.Samuel Strober specializes in the treatment of autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. He has practiced rheumatology at Stanford for more than 30 years. He has special interests in the treatment of lupus kidney disease, and in eliminating the lifelong need for immunosuppressive drugs of organ transplant patients. He does not see patients in the Stanford out-patient clinics, but consults on Stanford in-patients with autoimmune disease and inflammatory arthritis. In addition, he consults on the medical tests that are required to determine the diagnosis and treatment of these diseases.
Dr. Strober's laboratory and clinical research interests are in the area of the molecular and cellular basis of the prevention of graft versus host disease while maintaining graft anti-tumor activity in recipients of bone marrow transplants, the induction of tolerance in recipients of combined organ and hematopoietic cell transplants, and the effective treatment of solid tumors and lymphoma with local tumor radiation regimens that induce potent anti-tumor immune responses. His laboratory research has been translated into ongoing clinical trials of organ and bone marrow transplantation at Stanford.

Clinical Focus


  • Immunology and Rheumatology
  • Bone Marrow and Organ Transplantation
  • Immunotherapy of Cancer
  • Rheumatology

Academic Appointments


Administrative Appointments


  • Program Director, NIH Program Project Grant (2004 - Present)
  • Member, Stanford Diabetes Research Center, Stanford University (2018 - Present)

Professional Education


  • Fellowship:University of Oxford Medical Sciences Division Registrar (1965) UK
  • Residency:Stanford University School of Medicine Registrar (1971) CA
  • Residency:Massachusetts General Hospital (1967) MA
  • Internship:Massachusetts General Hospital (1967) MA
  • Medical Education:Harvard Medical School (1966) MA

Current Research and Scholarly Interests


Research Interests:
Our interests are in the area of cellular immunology, and the regulatory interactions between subpopulations of immune cells. In particular, we are interested in the identification, function, and molecular mechanisms by which some subpopulations of lymphocytes amplify the immune response and some such as natural killer T cells (NKT cells) and regulatory T cells (Treg cells) suppress it. Investigation into interactions of the cells during the immune response to organ and bone marrow transplants and in tumor immunity is a major focus of the laboratory research. Developing therapeutic strategies for clinical organ transplantation in humans with hematologic or solid tumors based on these principles is a major goal. Specific areas of research are as follows:

(i) Immune tolerance to organ and bone marrow transplants: Immune tolerance is recognized to be the paralysis of the immune system in its response to a given antigen, the development of anergy, or antigen-specific suppressor cells. Our research programs are studying these mechanisms at the cellular and molecular levels in laboratory animals and humans that are made tolerant to foreign organ or bone marrow transplants. In the case of bone marrow transplants, the goal is to prevent graft vs. host disease while maintaining graft anti-tumor activity.

(ii) In the case of organ transplants, the goal is to achieve acceptance of the transplants in the absence of maintenance immonosuppressive drugs. Tolerance is achieved by establishment of mixed chimerism. Our mouse models have been translated to clinical studies in which tolerance and prevention of graft vs host disease have been achieved. Our laboratory is involved in identifying those cells (NKTcells, Treg cells, myeloid derived suppressor cells, dendritic cells) involved in the induction and maintenance of immune tolerance with regard to their surface receptors, effector functions, and the nature of secreted molecules which mediate their function. We have shown that interactions of these cells are important suppressors of tumor immunity and promoters of organ transplantation tolerance.

(iii) In the case of hematologic and solid tumors, the goal is to eliminate cells that mediate immune tolerance in the tumor microenvironment such that effector T cells can kill the tumor cells. Target cells for depletion include myeloid derived suppressor cells, Treg cells, and tolerogenic dendritic cells.

Clinical Trials


  • CD8+ Memory T-Cells as Consolidative Therapy After Donor Non-myeloablative Hematopoietic Cell Transplant in Treating Patients With Leukemia or Lymphoma Recruiting

    This phase II trial studies how well cluster of differentiation 8 (CD8)+ memory T-cells work as a consolidative therapy following a donor non-myeloablative hematopoietic cell transplant in treating patients with leukemia or lymphoma. Giving total lymphoid irradiation and anti-thymocyte globulin before a donor hematopoietic cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft-versus-host disease). Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from happening. Once the donated stem cells begin working, the patient's immune system may see the remaining cancer cells as not belonging in the patient's body and destroy them. Giving an infusion of the donor's white blood cells, such as CD8+ memory T-cells, may boost this effect and may be an effective treatment to kill any cancer cells that may be left in the body (consolidative therapy).

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  • Combined Blood Stem Cell and Kidney Transplant of One Haplotype Match Living Donor Pairs. Recruiting

    The Stanford Medical Center Program in Multi-Organ Transplantation and the Division of Bone marrow Transplantation are enrolling patients into a research study to determine if donor stem cells given after a living related one Haplotype match kidney transplantation will change the immune system such that immunosuppressive drugs can be completely withdrawn.

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  • Inducing Graft Tolerance in HLA Haplotype Matched Related and 3 Ag Matched Unrelated Living Donor Kidney Transplantation Recruiting

    This research study is to determine if donor blood stem cells given after living, related, HLA antigen (Ag) haplotype match or living, unrelated, 3 HLA antigen matched (HLA-A, -B, and -DR) donor kidney transplantation will change the immune system such that immunosuppressive drugs can be completely withdrawn or reduced to minimal dose without kidney rejection.

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  • Allogeneic Transplantation From Related Haploidentical Donors Not Recruiting

    The purpose of the study is to evaluate the feasibility and safety of transplanting CD34+ selected hematopoietic cells from a haploidentical related donor following a nonmyeloablative regimen of total lymphoid irradiation (TLI) and antithymocyte globulin (ATG).

    Stanford is currently not accepting patients for this trial. For more information, please contact BMT Referrals, (650) 723 - 0822.

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  • Delayed Blood Stem Transplantation in HLA Matched Kidney Transplant Recipients to Eliminate Immunosuppressive Drugs. Not Recruiting

    The study will determine whether patients with functioning Human Leukocyte Antigen (HLA) matched kidney transplants for at least one year and who want to discontinue immunosuppressive drugs can be treated with Total Lymphoid Irradiation (TLI) and rabbit Anti-Thymocyte Globulin (rATG) and an HLA matched donor hematopoietic progenitor cell infusion such that their drugs are successfully withdrawn while maintaining normal renal function.

    Stanford is currently not accepting patients for this trial.

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  • Donor Peripheral Stem Cell Transplant in Treating Patients With Hematolymphoid Malignancies Not Recruiting

    This phase I trial studies the side effects and the best dose of donor CD8+ memory T-cells in treating patients with hematolymphoid malignancies. Giving low dose of chemotherapy before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-cancer effects). Giving an infusion of the donor's T cells (donor lymphocyte infusion) after the transplant may help increase this effect

    Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, 650-723-0822.

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  • Immunostimulatory CpG SD-101 + RT in Recurrent/Progressive Lymphoma After Allogeneic Hematopoietic Cell Transplantation (HCT) Not Recruiting

    For patients with lymphoma that recurs after chemotherapy, bone marrow transplantation using cells from a healthy donor represents potentially curative treatment. In these individuals, cure is possible because transplantation of healthy donor immune cells can fight the lymphoma in the patient. The goal of this work is to test a strategy that activates the healthy donor immune cells so that they more effectively fight lymphoma and can result in an increased cure rate for these patients. Our group has previously studied CpG, an immune activating medication, in patients with lymphoma and demonstrated modest anti-tumor responses. We now have a more potent form of CpG which we intend to test to see if it will better activate the donor immune cells and result in shrinkage of tumor throughout the entire body, not just at the injected site.

    Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, 650-723-0822.

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  • Kidney and Blood Stem Cell Transplantation That Eliminates Requirement for Immunosuppressive Drugs Not Recruiting

    The Stanford Medical Center Program in Multi-Organ Transplantation and the Division of Bone Marrow Transplantation are enrolling patients into a research study to determine if blood stem cells injected after kidney transplantation, in combination with lymphoid irradiation ,will change the immune system such that immunosuppressive drugs can be completely withdrawn. Patients must have a healthy, completely human leukocyte antigen (HLA)-matched brother or sister as the organ and stem cell donor. One to two months before kidney transplant surgery, blood stem cells will be removed from the donor and the cells will be frozen. After transplant surgery, the recipient will receive radiation and anti-T cell antibody treatments for two weeks to prepare for injection of the stem cells. The stem cells will be injected at the end of the two-week treatment. If the stem cells persist in the recipient, immunosuppressive drugs will be gradually reduced until they are withdrawn completely at least six months after transplantation. Patients will be followed in the Stanford clinics for transplant patients. Patients who live outside of the San Francisco Bay Area must remain near Stanford for six weeks after transplant surgery.

    Stanford is currently not accepting patients for this trial. For more information, please contact Stephan Busque, MD, 650-498-6189.

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  • TLI & ATG for Non-Myeloablative Allogeneic Transplantation for MDS and MPD Not Recruiting

    To evaluate the feasibility and safety of TLI/ATG conditioning for allogeneic HCT for elderly patients with advanced stage MDS and MPD.

    Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, 650-723-0822.

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2018-19 Courses


Graduate and Fellowship Programs


All Publications


  • Impact of Immunosuppressive Drug Withdrawal on Persistent Mixed Chimerism in Recipients of HLA Haplo-Identical Kidney and Hematopoietic Cell Transplants. Busque, S., Scandling, J., Lowsky, R., Shizuru, J., Meyer, E., Jensen, K., Shori, A., Hoppe, R., Engleman, E., Strober, S. WILEY. 2019: 348
  • Persistent Mixed Chimerism, Immune Reconstitution, and Tolerance in Recipients of HLA Matched Kidney and Hematopoietic Cell Transplants. Busque, S., Scandling, J., Lowsky, R., Shizuru, J., Meyer, E., Jensen, K., Shori, A., Hoppe, R., Engleman, E., Pham, T., Strober, S. WILEY. 2019: 348–49
  • Summary of the Third International Workshop on Clinical Tolerance AMERICAN JOURNAL OF TRANSPLANTATION Kawai, T., Leventhal, J., Wood, K., Strober, S. 2019; 19 (2): 324–30

    Abstract

    The Third International Workshop on Clinical Tolerance was held in Stanford, California, September 8-9, 2017. This is a summary of Workshop presentations of clinical trials designed to withdraw or minimize immunosuppressive (IS) drugs in kidney and liver transplant patients without subsequent evidence of rejection. All clinical protocols had in common the use of donor or recipient cell therapy combined with organ transplantation. Tolerance to HLA matched and mismatched living donor kidney transplants with complete withdrawal of IS drugs without subsequent rejection for up to 14 years of observation was achieved in more than 50 patients enrolled in trials in four medical centers after the establishment of transient or persistent chimerism. Complete IS drug withdrawal without chimerism was reported in a prospective trial of liver transplantation combined with injection of regulatory T cells. IS drug minimization without rejection was reported in recipients of living donor kidney transplants enrolled in the One Study consortium after injection of recipient regulatory T cells, or injection of donor regulatory monocytes or dendritic cells. In conclusion, considerable progress has been made in achieving IS drug withdrawal after cell therapy in recipients of organ transplants.

    View details for PubMedID 30133954

    View details for PubMedCentralID PMC6349553

  • Nonmyeloablative Allogeneic Transplantation Using TLI-ATG Conditioning for Lymphoid and Myeloid Malignancies: Mature Follow-up from a Large, Single Institution Cohort Spinner, M. A., Kennedy, V. E., Tamaresis, J. S., Lavori, P. W., Elder, L. V., Arai, S., Johnston, L. J., Meyer, E. H., Miklos, D. B., Muffly, L. S., Negrin, R. S., Rezvani, A. R., Shizuru, J. A., Weng, W., Hoppe, R. T., Strober, S., Lowsky, R. AMER SOC HEMATOLOGY. 2018
  • A Proinflammatory Invariant Natural Killer T Cells Phenotypic State Associates with Human Graft-Versus-Host Disease Onset and Response Erkers, T., Xei, B., Kenyon, L., Rieck, M., Basina, M., Jensen, K., Strober, S., Negrin, R. S., Maecker, H. T., Meyer, E. H. AMER SOC HEMATOLOGY. 2018
  • Relationship Between Mixed Chimerism and Acceptance of HLA-matched and -Mismatched Kidney Transplants after Withdrawal of Immunosuppressive Drugs Busque, S., Scandling, J., Lowsky, R., Shizuru, J., Jensen, K., Shori, A., Hoppe, R., Engleman, E., Meyer, E., Strober, S. LIPPINCOTT WILLIAMS & WILKINS. 2018: S393
  • Tomotherapy and Hematopoietic Stem Cells for Tolerance to Kidney Transplants in Rhesus Macaques Kaufman, D. B., Haynes, L., Burlingham, W., Hematti, P., Forrest, L., Post, J., Jankowska-Gan, E., Jensen, K., Strober, S. LIPPINCOTT WILLIAMS & WILKINS. 2018: S262
  • Relationship between Mixed Chimerism and Acceptance of HLA-Matched and Mismatched Kidney Transplants after Withdrawal of Immunosuppressive Drugs. Scandling, J., Busque, S., Lowsky, R., Shizuru, J., Jensen, K., Shori, A., Engleman, E., Meyer, E., Hoppe, R., Strober, S. WILEY. 2018: 470
  • Tomotherapy and Donor Hematopoietic Cells for Tolerance to Kidney Transplants in Rhesus Macaques. Kaufman, D., Haynes, L., Hematti, P., Burlingham, W., Forest, L., Post, J., Redfield, R., Fernandez, L., D'Alessandro, A., Haynes, J., Jensen, K., Strober, S. WILEY. 2018: 614
  • Proceedings From the Fourth Haploidentical Stem Cell Transplantation Symposium (HAPL02016), San Diego, California, December 1, 2016 BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Al Malki, M. M., Jones, R., Ma, Q., Lee, D., Reisner, Y., Miller, J. S., Lang, P., Hongeng, S., Hari, P., Strober, S., Yu, J., Maziarz, R., Mavilio, D., Roy, D., Bonini, C., Champlin, R. E., Fuchs, E. J., Ciurea, S. O. 2018; 24 (5): 895–908

    Abstract

    The resurgence of haploidentical stem cell transplantation (HaploSCT) over the last decade is one of the most important advances in the field of hematopoietic stem cell transplantation (HSCT). The modified platforms of T cell depletion either ex vivo (CD34+ cell selection, "megadoses" of purified CD34+ cells, or selective depletion of T cells) or newer platforms of in vivo depletion of T cells, with either post-transplantation high-dose cyclophosphamide or intensified immune suppression, have contributed to better outcomes, with survival similar to that in HLA-matched donor transplantation. Further efforts are underway to control viral reactivation using modified T cells, improve immunologic reconstitution, and decrease the relapse rate post-transplantation using donor-derived cellular therapy products, such as genetically modified donor lymphocytes and natural killer cells. Improvements in treatment-related mortality have allowed the extension of haploidentical donor transplants to patients with hemoglobinopathies, such as thalassemia and sickle cell disease, and the possible development of platforms for immunotherapy in solid tumors. Moreover, combining HSCT from a related donor with solid organ transplantation could allow early tapering of immunosuppression in recipients of solid organ transplants and hopefully prevent organ rejection in this setting. This symposium summarizes some of the most important recent advances in HaploSCT and provides a glimpse in the future of fast growing field.

    View details for PubMedID 29339270

  • Infusion of donor-derived CD8(+) memory T cells for relapse following allogeneic hematopoietic cell transplantation BLOOD ADVANCES Muffly, L., Sheehan, K., Armstrong, R., Jensen, K., Tate, K., Rezvani, A. R., Miklos, D., Arai, S., Shizuru, J., Johnston, L., Meyer, E., Weng, W., Laport, G. G., Negrin, R. S., Strober, S., Lowsky, R. 2018; 2 (6): 681–90

    Abstract

    Murine models showed that CD8+CD44hi memory T (TM) cells could eradicate malignant cells without inducing graft-versus-host disease (GVHD). We evaluated the feasibility and safety of infusing freshly isolated and purified donor-derived phenotypic CD8+ TM cells into adults with disease relapse after allogeneic hematopoietic cell transplantation (HCT). Phenotypic CD8 TM cells were isolated after unmobilized donor apheresis using a tandem immunomagnetic selection strategy of CD45RA depletion followed by CD8+ enrichment. Fifteen patients received CD8+ TM cells at escalating doses (1 × 106, 5 × 106, or 10 × 106 cells per kg). Thirteen received cytoreduction before CD8+ TM cell infusion, and 9 had active disease at the time of infusion. Mean yield and purity of the CD8+ TM infusion were 38.1% and 92.8%, respectively; >90% had CD8+ T effector memory phenotype, cytokine expression, and secretion profile. No adverse infusional events or dose-limiting toxicities occurred; GVHD developed in 1 patient (grade 2 liver). Ten patients (67%) maintained or achieved response (7 complete response, 1 partial response, 2 stable disease) for at least 3 months after infusion; 4 of the responders had active disease at the time of infusion. With a median follow-up from infusion of 328 days (range, 118-1328 days), median event-free survival and overall survival were 4.9 months (95% confidence interval [CI], 1-19.3 months) and 19.6 months (95% CI, 5.6 months to not reached), respectively. Collection and enrichment of phenotypic CD8+ TM cells is feasible, well tolerated, and associated with a low incidence of GVHD when administered as a manipulated infusion of donor lymphocytes in patients who have relapsed after HCT. This trial was registered at www.clinicaltrials.gov as #NCT01523223.

    View details for PubMedID 29572391

  • Macrochimerism and clinical transplant tolerance. Human immunology Scandling, J. D., Busque, S., Lowsky, R., Shizuru, J., Shori, A., Engleman, E., Jensen, K., Strober, S. 2018

    Abstract

    Current theory holds that macrochimerism is essential to the development of transplant tolerance. Hematopoietic cell transplantation from the solid organ donor is necessary to achieve macrochimerism. Over the last 10-20 years, trials of tolerance induction with combined kidney and hematopoietic cell transplantation have moved from the preclinical to the clinical arena. The achievement of macrochimerism in the clinical setting is challenging, and potentially toxic due to the conditioning regimen necessary to hematopoietic cell transplantation and due to the risk of graft-versus-host disease. There are differences in chimerism goals and methods of the three major clinical stage tolerance induction strategies in both HLA-matched and HLA-mismatched living donor kidney transplantation, with consequent differences in efficacy and safety. The Stanford protocol has proven efficacious in the induction of tolerance in HLA-matched kidney transplantation, allowing cessation of immunosuppressive drug therapy in 80% of study participants, with the safety profile of conventional transplantation. In HLA-mismatched transplantation, multi-lineage macrochimerism of over a year's duration can now be consistently achieved with the Stanford protocol, with complete withdrawal of immunosuppressive drug therapy during the second post-transplant year as the next experimental step and test of tolerance.

    View details for PubMedID 29330112

  • Accelerated, but not conventional, radiotherapy of murine B-cell lymphoma induces potent T cell-mediated remissions. Blood advances Dutt, S., Atallah, M. B., Minamida, Y., Filatenkov, A., Jensen, K. P., Iliopoulou, B. P., Tamosiuniene, R., Waters, J., Engleman, E. G., Strober, S. 2018; 2 (19): 2568–80

    Abstract

    Conventional local tumor irradiation (LTI), delivered in small daily doses over several weeks, is used clinically as a palliative, rather than curative, treatment for chemotherapy-resistant diffuse large B-cell lymphoma (DLBCL) for patients who are ineligible for hematopoietic cell transplantation. Our goal was to test the hypothesis that accelerated, but not conventional, LTI would be more curative by inducing T cell-mediated durable remissions. We irradiated subcutaneous A20 and BL3750 lymphoma tumors in mice with a clinically relevant total radiation dose of 30 Gy LTI, delivered in 10 doses of 3 Gy over 4 days (accelerated irradiation) or as 10 doses of 3 Gy over 12 days (conventional irradiation). Compared with conventional LTI, accelerated LTI resulted in more complete and durable tumor remissions. The majority of these mice were resistant to rechallenge with lymphoma cells, demonstrating the induction of memory antitumor immunity. The increased efficacy of accelerated LTI correlated with higher levels of tumor cell necrosis vs apoptosis and expression of "immunogenic cell death" markers, including calreticulin, heat shock protein 70 (Hsp70), and Hsp90. Accelerated LTI-induced remissions were not seen in immunodeficient Rag-2-/- mice, CD8+ T-cell-depleted mice, or Batf-3-/- mice lacking CD8α+ and CD103+ dendritic cells. Accelerated, but not conventional, LTI in immunocompetent hosts induced marked increases in tumor-infiltrating CD4+ and CD8+ T cells and MHCII+CD103+CD11c+ dendritic cells and corresponding reductions in exhausted PD-1+Eomes+CD8+ T cells and CD4+CD25+FOXP3+ regulatory T cells. These findings raise the possibility that accelerated LTI can provide effective immune control of human DLBCL.

    View details for PubMedID 30301812

  • The Promise of Targeting Macrophages in Cancer Therapy CLINICAL CANCER RESEARCH Brown, J., Recht, L., Strober, S. 2017; 23 (13): 3241–50

    Abstract

    Cancer therapy has developed around the concept of killing, or stopping the growth of, the cancer cells. Molecularly targeted therapy is the modern expression of this paradigm. Increasingly, however, the realization that the cancer has co-opted the normal cells of the stroma for its own survival has led to the concept that the tumor microenvironment (TME) could be targeted for effective therapy. In this review, we outline the importance of tumor-associated macrophages (TAM), a major component of the TME, in the response of tumors to cancer therapy. We discuss the normal role of macrophages in wound healing, the major phenotypes of TAMs, and their role in blunting the efficacy of cancer treatment by radiation and anticancer drugs, both by promoting tumor angiogenesis and by suppressing antitumor immunity. Finally, we review the many preclinical studies that have shown that the response of tumors to irradiation and anticancer drugs can be improved, sometimes markedly so, by depleting TAMs from tumors or by suppressing their polarization from an M1 to an M2 phenotype. The data clearly support the validity of clinical testing of combining targeting TAMs with conventional therapy. Clin Cancer Res; 23(13); 3241-50. ©2017 AACR.

    View details for PubMedID 28341752

    View details for PubMedCentralID PMC5529121

  • Relationship Between Mixed Chimerism and Tolerance in HLA-Matched and -Mismatched Recipients of Kidney and Hematopoietic Cell Transplants Busque, S., Scandling, J., Shizuru, J., Lowsky, R., Shori, A., Kent, J., Engleman, E., Strober, S. WILEY. 2017: 276
  • Tolerogenic interactions between CD8(+) dendritic cells and NKT cells prevent rejection of bone marrow and organ grafts BLOOD Hongo, D., Tang, X., Zhang, X., Engleman, E. G., Strober, S. 2017; 129 (12): 1718-1728

    Abstract

    The combination of total lymphoid irradiation and anti-T-cell antibodies safely induces immune tolerance to combined hematopoietic cell and organ allografts in humans. Our mouse model required host natural killer T (NKT) cells to induce tolerance. Because NKT cells normally depend on signals from CD8(+) dendritic cells (DCs) for their activation, we used the mouse model to test the hypothesis that, after lymphoid irradiation, host CD8(+) DCs play a requisite role in tolerance induction through interactions with NKT cells. Selective deficiency of either CD8(+) DCs or NKT cells abrogated chimerism and organ graft acceptance. After radiation, the CD8(+) DCs increased expression of surface molecules required for NKT and apoptotic cell interactions and developed suppressive immune functions, including production of indoleamine 2,3-deoxygenase. Injection of naive mice with apoptotic spleen cells generated by irradiation led to DC changes similar to those induced by lymphoid radiation, suggesting that apoptotic body ingestion by CD8(+) DCs initiates tolerance induction. Tolerogenic CD8(+) DCs induced the development of tolerogenic NKT cells with a marked T helper 2 cell bias that, in turn, regulated the differentiation of the DCs and suppressed rejection of the transplants. Thus, reciprocal interactions between CD8(+) DCs and invariant NKT cells are required for tolerance induction in this system that was translated into a successful clinical protocol.

    View details for DOI 10.1182/blood-2016-07-723015

    View details for Web of Science ID 000397297300023

    View details for PubMedCentralID PMC5364338

  • Tolerogenic interactions between CD8+ dendritic cells and NKT cells prevent rejection of bone marrow and organ grafts. Blood Hongo, D., Tang, X., Zhang, X., Engleman, E. G., Strober, S. 2017

    Abstract

    The combination of total lymphoid irradiation and anti-T-cell antibodies safely induces immune tolerance to combined hematopoietic cell and organ allografts in humans. Our mouse model required host natural killer T (NKT) cells to induce tolerance. Because NKT cells normally depend on signals from CD8(+) dendritic cells (DCs) for their activation, we used the mouse model to test the hypothesis that, after lymphoid irradiation, host CD8(+) DCs play a requisite role in tolerance induction through interactions with NKT cells. Selective deficiency of either CD8(+) DCs or NKT cells abrogated chimerism and organ graft acceptance. After radiation, the CD8(+) DCs increased expression of surface molecules required for NKT and apoptotic cell interactions and developed suppressive immune functions, including production of indoleamine 2,3-deoxygenase. Injection of naive mice with apoptotic spleen cells generated by irradiation led to DC changes similar to those induced by lymphoid radiation, suggesting that apoptotic body ingestion by CD8(+) DCs initiates tolerance induction. Tolerogenic CD8(+) DCs induced the development of tolerogenic NKT cells with a marked T helper 2 cell bias that, in turn, regulated the differentiation of the DCs and suppressed rejection of the transplants. Thus, reciprocal interactions between CD8(+) DCs and invariant NKT cells are required for tolerance induction in this system that was translated into a successful clinical protocol.

    View details for DOI 10.1182/blood-2016-07-723015

    View details for PubMedID 28096089

  • HLA-mismatched unrelated donor transplantation using TLI-ATG conditioning has a low risk of GVHD and potent antitumor activity. Blood advances Spinner, M. A., Fernández-Viña, M., Creary, L. E., Quinn, O., Elder, L., Arai, S., Johnston, L. J., Meyer, E. H., Miklos, D. B., Muffly, L. S., Negrin, R. S., Shizuru, J. A., Weng, W. K., Laport, G. G., Strober, S., Lowsky, R., Rezvani, A. R. 2017; 1 (17): 1347–57

    Abstract

    Many patients lack a fully HLA-matched donor for hematopoietic cell transplantation (HCT), and HLA mismatch is typically associated with inferior outcomes. Total lymphoid irradiation and antithymocyte globulin (TLI-ATG) is a nonmyeloablative conditioning regimen that is protective against graft-versus-host disease (GVHD), and we hypothesized that the protective effect would extend beyond HLA-matched donors. We report outcomes for all consecutively transplanted patients at Stanford University from December 2001 through May 2015 who received TLI-ATG conditioning and HCTs from 8 to 9 out of 10 HLA-mismatched unrelated donors (MMUDs, N = 72) compared with 10 out of 10 HLA-matched unrelated donors (MUDs, N = 193). The median age of the patients was 60 years with a median follow-up of 2 years, and there was a similar distribution of lymphoid and myeloid malignancies in both cohorts. There were no significant differences between MMUD and MUD cohorts in overall survival (46% vs 46% at 5 years, P = .86), disease-free survival (38% vs 28% at 5 years, P = .25), nonrelapse mortality (17% vs 12% at 2 years, P = .34), acute GVHD grades III-IV (6% vs 3% at day +100, P = .61), or chronic GVHD (39% vs 35% at 5 years, P = .49). There was a trend toward less relapse in the MMUD cohort (45% vs 60% at 5 years, hazard ratio: 0.71, P = .094), which was significant for patients with lymphoid malignancies (29% vs 57% at 5 years, hazard ratio: 0.55, P = .044). Achieving full donor chimerism was strongly associated with lower relapse rates. TLI-ATG conditioning may overcome the traditionally poorer outcome associated with HLA-mismatched donors and may be particularly well suited for patients with lymphoid malignancies who lack HLA-matched donors.

    View details for PubMedID 29296777

  • Phase I Study of CD8 Memory T-Cell Donor Lymphocyte Infusion for Relapse of Hematologic Malignancies Following Matched Related Donor Allogeneic Hematopoietic Cell Transplantation Muffly, L. S., Sheehan, K., Armstrong, R., Tate, K., Tudisco, C., Rezvani, A. R., Miklos, D., Arai, S., Shizuru, J., Johnston, L., Meyer, E., Weng, W., Laport, G. G., Negrin, R. S., Strober, S., Lowsky, R. AMER SOC HEMATOLOGY. 2016
  • Allogeneic Transplants from HLA-Mismatched Unrelated Donors Using Total Lymphoid Irradiation and Antithymocyte Globulin Conditioning Retain a Low Risk of Graft-Versus-Host Disease and Non-Relapse Mortality with at Least As Potent Anti-Tumor Activity As with Matched Unrelated Donors Spinner, M. A., Vina, M., Elder, L., Arai, S., Johnston, L., Meyer, E., Miklos, D., Muffly, L., Negrin, R. S., Shizuru, J., Weng, W., Laport, G. G., Strober, S., Lowsky, R., Rezvani, A. R. AMER SOC HEMATOLOGY. 2016
  • Immunosuppressive myeloid cells in patients given combined kidney and hematopoietic cell transplants in a tolerance protocol with TLI and ATG conditioning Jensen, K., Scandling, J., Busque, S., Shizuru, J., Lowsky, R., Saraswathula, A., Sheehan, K., Shori, A., Engleman, E., Strober, S. LIPPINCOTT WILLIAMS & WILKINS. 2016: S5
  • Relationship between mixed chimerism and clinical tolerance after combined kidney and hematopoietic cell transplantation using total lymphoid irradiation and antithymocyte globulin conditioning Busque, S., Scandling, J. D., Shizuru, J., Lowsky, R., Shori, A., Jensen, K., Engleman, E., Strober, S. LIPPINCOTT WILLIAMS & WILKINS. 2016: S245
  • Tolerogenic Interactions Between Host CD8(+)Myeloid Dendritic Cells and Natural Killer T Cells Are Required for Acceptance of Combined Organ and Bone Marrow Transplants After TLI Conditioning. Apum, D., Zhang, X., Engleman, E., Strober, S. WILEY-BLACKWELL. 2016: 370
  • Use of hematopoietic cell transplants to achieve tolerance in patients with solid organ transplants BLOOD Strober, S. 2016; 127 (12): 1539-1543

    Abstract

    The goals of tolerance in patients with solid organ transplants are to eliminate the lifelong need for immunosuppressive (IS) drugs and to prevent graft loss due to rejection or drug toxicity. Tolerance with complete withdrawal of IS drugs has been achieved in recipients of HLA-matched and mismatched living donor kidney transplants in 3 medical centers using hematopoietic cell transplants to establish mixed or complete chimerism.

    View details for DOI 10.1182/blood-2015-12-685107

    View details for Web of Science ID 000373505600008

    View details for PubMedID 26796362

    View details for PubMedCentralID PMC4807420

  • Long-Term Outcomes of AML Patients Using Total Lymphoid Irradiation with Anti-Thymocyte Globulin Nakasone, H., Miklos, D. B., Meyer, E., Rezvani, A., Muffly, L., Weng, W., Arai, S., Johnston, L., Laport, G. G., Shizuru, J. A., Negrin, R., Strober, S., Lowsky, R. ELSEVIER SCIENCE INC. 2016: S204–S205
  • Disruption of evasive immune cell microenvironment in tumors reflects immunity induced by radiation therapy ONCOIMMUNOLOGY Filatenkov, A., Baker, J., Strober, S. 2016; 5 (2): e1072673

    Abstract

    Radiation administered to murine colon tumors induced durable remissions that were dependent on CD4+ and CD8+ T cell immunity, and antigen cross priming CD8+ dendritic cells (DCs). Remissions were associated with marked reductions in the infiltration of myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) and Treg cells, and a marked increase in CD8+ T cells.

    View details for PubMedID 27057471

  • A Cost Analysis of Tolerance Induction for Two-Haplotype Match Kidney Transplant Recipients AMERICAN JOURNAL OF TRANSPLANTATION Erickson, K. F., Winkelmayer, W. C., Busque, S., Lowsky, R., Scandling, J. D., Strober, S. 2016; 16 (1): 371–73

    View details for PubMedID 26551201

  • Donor-Derived CIK Cell Infusion As Consolidative Therapy after Non-Myeloablative Allogeneic Transplant in Patients with Myeloid Neoplasms Narayan, R., Benjamin, J., Laport, G., Tian, L., Tate, K., Elder, L., Galvez, L., Armstrong, R., Sheehan, K., Lowsky, R., Arai, S., Johnston, L., Miklos, D., Muffly, L. S., Rezvani, A. R., Shizuru, J., Weng, W., Strober, S., Negrin, R., Meyer, E. AMER SOC HEMATOLOGY. 2015
  • Allogeneic hematopoietic cell transplantation after failed autologous transplant for lymphoma using TLI and anti-thymocyte globulin conditioning BONE MARROW TRANSPLANTATION Rezvani, A. R., Kanate, A. S., Efron, B., Chhabra, S., Kohrt, H. E., Shizuru, J. A., Laport, G. G., Miklos, D. B., Benjamin, J. E., JOHNSTON, L. J., Arai, S., Weng, W., Negrin, R. S., Strober, S., Lowsky, R. 2015; 50 (10): 1286-1292

    Abstract

    We describe 47 patients with lymphoma and failed prior autologous hematopoietic cell transplantation (HCT) who received TLI-ATG (anti-thymocyte globulin) conditioning followed by allogeneic HCT. Thirty-two patients had non-Hodgkin lymphoma (NHL; diffuse large B-cell lymphoma (n=19), T-cell NHL (n=6), mantle cell lymphoma (n=4) or other B-cell subtypes (n=3)), and 15 had Hodgkin lymphoma. The median follow-up was 4.9 (range, 2.1-11.9) years. The cumulative incidence of grade II-IV acute GvHD at day +100 was 12%, and the cumulative incidence of extensive chronic GvHD at 1 year was 36%. The 3-year cumulative incidences of overall survival (OS), PFS and non-relapse mortality (NRM) were 81%, 44% and 7%, respectively. Fifteen patients died (relapse, n=10; NRM, n=5). Among the 25 patients with relapse after allogeneic HCT, 11 (44%) achieved durable (>1 year) CRs following donor lymphocyte infusion or chemoradiotherapy. The majority of surviving patients (75%; n=24) were able to discontinue all immunosuppression. For patients with relapsed lymphoma after autologous HCT, allogeneic HCT using TLI-ATG conditioning is a well-tolerated, predominantly outpatient therapy with low NRM (7% at 3 years), a low incidence of GvHD, durable disease control and excellent OS (81% at 3 years).

    View details for DOI 10.1038/bmt.2015.149

    View details for PubMedID 26146806

  • Ablative Tumor Radiation Can Change the Tumor Immune Cell Microenvironment to Induce Durable Complete Remissions. Clinical cancer research Filatenkov, A., Baker, J., Mueller, A. M., Kenkel, J., Ahn, G., Dutt, S., Zhang, N., Kohrt, H., Jensen, K., Dejbakhsh-Jones, S., Shizuru, J. A., Negrin, R. N., Engleman, E. G., Strober, S. 2015; 21 (16): 3727-3739

    Abstract

    The goals of the study were to elucidate the immune mechanisms that contribute to desirable complete remissions of murine colon tumors treated with single radiation dose of 30 Gy. This dose is at the upper end of the ablative range used clinically to treat advanced or metastatic colorectal, liver, and non-small cell lung tumors.Changes in the tumor immune microenvironment of single tumor nodules exposed to radiation were studied using 21-day (>1 cm in diameter) CT26 and MC38 colon tumors. These are well-characterized weakly immunogenic tumors.We found that the high-dose radiation transformed the immunosuppressive tumor microenvironment resulting in an intense CD8(+) T-cell tumor infiltrate, and a loss of myeloid-derived suppressor cells (MDSC). The change was dependent on antigen cross-presenting CD8(+) dendritic cells, secretion of IFNγ, and CD4(+)T cells expressing CD40L. Antitumor CD8(+) T cells entered tumors shortly after radiotherapy, reversed MDSC infiltration, and mediated durable remissions in an IFNγ-dependent manner. Interestingly, extended fractionated radiation regimen did not result in robust CD8(+) T-cell infiltration.For immunologically sensitive tumors, these results indicate that remissions induced by a short course of high-dose radiotherapy depend on the development of antitumor immunity that is reflected by the nature and kinetics of changes induced in the tumor cell microenvironment. These results suggest that systematic examination of the tumor immune microenvironment may help in optimizing the radiation regimen used to treat tumors by adding a robust immune response. Clin Cancer Res; 21(16); 3727-39. ©2015 AACR.

    View details for DOI 10.1158/1078-0432.CCR-14-2824

    View details for PubMedID 25869387

  • Stable and Unstable Chimerism During Immunosuppressive Drug Withdrawal in Tolerant Recipients of HLA Matched Combined Kidney and Hematopoietic Cell Transplants Pham, T., Busque, S., Scandling, J., Shizuru, J., Asha, S., Strober, S. WILEY-BLACKWELL. 2015
  • An Economic Analysis of Tolerance Induction for Two-Haplotype Match Kidney Living Donor Transplant Recipients Erickson, K., Winkelmayer, W., Lowsky, R., Scandling, J., Strober, S. WILEY-BLACKWELL. 2015
  • Stable mixed chimerism and tolerance to human organ transplants. Chimerism Strober, S. 2015; 6 (1-2): 27–32

    Abstract

    Tolerance to combined kidney and hematopoietic cell transplant has been achieved in humans after establishment of mixed chimerism allowing for the withdrawal of immunosuppressive drugs. The seminal contributions of Ray Owen provided the scientific basis for the human protocol.

    View details for PubMedID 26855335

  • Chimerism, Graft Survival, and Withdrawal of Immunosuppressive Drugs in HLA Matched and Mismatched Patients After Living Donor Kidney and Hematopoietic Cell Transplantation. American journal of transplantation Scandling, J. D., Busque, S., Shizuru, J. A., Lowsky, R., Hoppe, R., Dejbakhsh-Jones, S., Jensen, K., Shori, A., Strober, J. A., Lavori, P., Turnbull, B. B., Engleman, E. G., Strober, S. 2015; 15 (3): 695-704

    Abstract

    Thirty-eight HLA matched and mismatched patients given combined living donor kidney and enriched CD34(+) hematopoietic cell transplants were enrolled in tolerance protocols using posttransplant conditioning with total lymphoid irradiation and anti-thymocyte globulin. Persistent chimerism for at least 6 months was associated with successful complete withdrawal of immunosuppressive drugs in 16 of 22 matched patients without rejection episodes or kidney disease recurrence with up to 5 years follow up thereafter. One patient is in the midst of withdrawal and five are on maintenance drugs. Persistent mixed chimerism was achieved in some haplotype matched patients for at least 12 months by increasing the dose of T cells and CD34(+) cells infused as compared to matched recipients in a dose escalation study. Success of drug withdrawal in chimeric mismatched patients remains to be determined. None of the 38 patients had kidney graft loss or graft versus host disease with up to 14 years of observation. In conclusion, complete immunosuppressive drug withdrawal could be achieved thus far with the tolerance induction regimen in HLA matched patients with uniform long-term graft survival in all patients.

    View details for DOI 10.1111/ajt.13091

    View details for PubMedID 25693475

  • Invariant natural killer T cells in lupus patients promote IgG and IgG autoantibody production EUROPEAN JOURNAL OF IMMUNOLOGY Shen, L., Zhang, H., Caimol, M., Benike, C. J., Chakravarty, E. F., Strober, S., Engleman, E. G. 2015; 45 (2): 612-623

    Abstract

    IgG autoantibodies, including antibodies to double-stranded DNA (dsDNA), are pathogenic in systemic lupus erythematosus (SLE), but the mechanisms controlling their production are not understood. To assess the role of invariant natural killer T (iNKT) cells in this process, we studied 44 lupus patients. We took advantage of the propensity of PBMCs from patients with active disease to spontaneously secrete IgG in vitro. Despite the rarity of iNKT cells in lupus blood (0.002-0.05% of CD3-positive T cells), antibody blockade of the conserved iNKT TCR or its ligand, CD1d, or selective depletion of iNKT cells, inhibited spontaneous secretion of total IgG and anti-dsDNA IgG by lupus PBMCs. Addition of anti-iNKT or anti-CD1d antibody to PBMC cultures also reduced the frequency of plasma cells, suggesting that lupus iNKT cells induce B-cell maturation. Like fresh iNKT cells, expanded iNKT-cell lines from lupus patients, but not healthy subjects, induced autologous B cells to secrete antibodies, including IgG anti-dsDNA. This activity was inhibited by anti-CD40L antibody, as well as anti-CD1d antibody, confirming a role for CD40L-CD40 and TCR-CD1d interactions in lupus iNKT-cell-mediated help. These results reveal a critical role for iNKT cells in B-cell maturation and autoantibody production in patients with lupus.

    View details for DOI 10.1002/eji.201444760

    View details for Web of Science ID 000349625400030

    View details for PubMedID 25352488

    View details for PubMedCentralID PMC4324163

  • Requirement for Interactions of Natural Killer T Cells and Myeloid-Derived Suppressor Cells for Transplantation Tolerance AMERICAN JOURNAL OF TRANSPLANTATION Hongo, D., Tang, X., Baker, J., Engleman, E. G., Strober, S. 2014; 14 (11): 2467-2477

    Abstract

    The goal of the study was to elucidate the cellular and molecular mechanisms by which a clinically applicable immune tolerance regimen of combined bone marrow and heart transplants in mice results in mixed chimerism and graft acceptance. The conditioning regimen of lymphoid irradiation and anti-T cell antibodies changed the balance of cells in the lymphoid tissues to create a tolerogenic microenvironment favoring the increase of natural killer T (NKT) cells, CD4+ CD25+ regulatory T cells and Gr-1+ CD11b+ myeloid-derived suppressor cells (MDSCs), over conventional T cells (Tcons). The depletion of MDSCs abrogated chimerism and tolerance, and add back of these purified cells was restorative. The conditioning regimen activated the MDSCs as judged by the increased expression of arginase-1, IL-4Rα and programmed death ligand 1, and the activated cells gained the capacity to suppress the proliferation of Tcons to alloantigens in the mixed leukocyte reaction. MDSC activation was dependent on the presence of host invariant NKT cells. The conditioning regimen polarized the host invariant NKT cells toward IL-4 secretion, and MDSC activation was dependent on IL-4. In conclusion, there was a requirement for MDSCs for chimerism and tolerance, and their suppressive function was dependent on their interactions with NKT cells and IL-4.

    View details for DOI 10.1111/ajt.12914

    View details for Web of Science ID 000344178800008

    View details for PubMedID 25311657

    View details for PubMedCentralID PMC4205183

  • Treatment of 4T1 Metastatic Breast Cancer with Combined Hypofractionated Irradiation and Autologous T-Cell Infusion. Radiation research Filatenkov, A., Baker, J., Müller, A. M., Ahn, G., Kohrt, H., Dutt, S., Jensen, K., Dejbakhsh-Jones, S., Negrin, R. S., Shizuru, J. A., Engleman, E. G., Strober, S. 2014; 182 (2): 163-169

    Abstract

    The goal of this study was to determine whether a combination of local tumor irradiation and autologous T-cell transplantation can effectively treat metastatic 4T1 breast cancer in mice. BALB/c mice were injected subcutaneously with luciferase-labeled 4T1 breast tumor cells and allowed to grow for 21 days, at which time metastases appeared in the lungs. Primary tumors were treated at that time with 3 daily fractions of 20 Gy of radiation each. Although this approach could eradicate primary tumors, tumors in the lungs grew progressively. We attempted to improve efficacy of the radiation by adding autologous T-cell infusions. Accordingly, T cells were purified from the spleens of tumor-bearing mice after completion of irradiation and cryopreserved. Cyclophosphamide was administered thereafter to induce lymphodepletion, followed by T-cell infusion. Although the addition of cyclophosphamide to irradiation did not improve survival or reduce tumor progression, the combination of radiation, cyclophosphamide and autologous T-cell infusion induced durable remissions and markedly improved survival. We conclude that the combination of radiation and autologous T-cell infusion is an effective treatment for metastatic 4T1 breast cancer.

    View details for DOI 10.1667/RR13471.1

    View details for PubMedID 24992165

  • Tolerance: One Transplant for Life TRANSPLANTATION Kawai, T., Leventhal, J., Madsen, J. C., Strober, S., Turka, L. A., Wood, K. J. 2014; 98 (2): 117–21

    Abstract

    Recently, The Transplantation Society convened a workshop to address the question, "What do we need to have in place to make tolerance induction protocols a 'standard of care' for organ transplant recipients over the next decade?" In a productive 2-day meeting, there was wide-ranging discussion on a broad series of topics, resulting in five consensus recommendations as follows: (1) establish a registry of results for patients enrolled in tolerance trials; (2) establish standardized protocols for sample collection and storage; (3) establish standardized biomarkers and assays; (4) include children 12 years and older in protocols that have been validated in adults; and (5) establish a task force to engage third-party payers in discussions of how to fund tolerance trials. Future planned workshops will focus on progress in implementing these recommendations and identifying other steps that the community needs to take.

    View details for PubMedID 24926829

    View details for PubMedCentralID PMC4101034

  • Cellular Based Immunodepletion and Tomotherapy for Induction of Immunosuppression in a Rhesus Macaque Renal Allotransplant Model Kempton, S., Haynes, L., Gan-Jankowska, E., Forrest, L., Hematti, P., Fernandez, L., Burlingham, W., Strober, S., Kaufman, D. LIPPINCOTT WILLIAMS & WILKINS. 2014: 289
  • Requirement for Interactions of Natural Killer T Cells and Myeloid Derived Suppressor Cells for Transplantation Tolerance Hongo, D., Tang, X., Baker, J., Strober, S. LIPPINCOTT WILLIAMS & WILKINS. 2014: 28
  • Tolerance, Mixed Chimerism, and Graft Survival in HLA Matched and Mismatched Recipients of Kidney and Hematopoietic Cell Transplants. Scandling, J., Busque, S., Shizuru, J., Lowsky, R., Dejbakhsh-Jones, S., Jensen, K., Shori, A., Turnbull, B., Engleman, E., Strober, S. LIPPINCOTT WILLIAMS & WILKINS. 2014: 901
  • Requirement for Interactions of Natural Killer T Cells and Myeloid Derived Suppressor Cells for Transplantation Tolerance. Hongo, D., Tang, X., Baker, J., Strober, S. WILEY-BLACKWELL. 2014: 28
  • Cellular Based Immunodepletion and Tomotherapy for Induction of Immunosuppression in a Rhesus Macaque Renal Allotransplant Model. Kempton, S., Haynes, L., Gan-Jankowska, E., Forrest, L., Hematti, P., Fernandez, L., Burlingham, W., Strober, S., Kaufman, D. WILEY-BLACKWELL. 2014: 289
  • Tolerance, Mixed Chimerism, and Graft Survival in HLA Matched and Mismatched Recipients of Kidney and Hematopoietic Cell Transplants. Scandling, J., Busque, S., Shizuru, J., Lowsky, R., Dejbakhsh-Jones, S., Jensen, K., Shori, A., Turnbull, B., Engleman, E., Strober, S. WILEY-BLACKWELL. 2014: 901
  • Ly108 expression distinguishes subsets of invariant NKT cells that help autoantibody production and secrete IL-21 from those that secrete IL-17 in lupus prone NZB/W mice. Journal of autoimmunity Tang, X., Zhang, B., Jarrell, J. A., Price, J. V., Dai, H., Utz, P. J., Strober, S. 2014; 50: 87-98

    Abstract

    Lupus is a systemic autoimmune disease characterized by anti-nuclear antibodies in humans and genetically susceptible NZB/W mice that can cause immune complex glomerulonephritis. T cells contribute to lupus pathogenesis by secreting pro-inflammatory cytokines such as IL-17, and by interacting with B cells and secreting helper factors such as IL-21 that promote production of IgG autoantibodies. In the current study, we determined whether purified NKT cells or far more numerous conventional non-NKT cells in the spleen of NZB/W female mice secrete IL-17 and/or IL-21 after TCR activation in vitro, and provide help for spontaneous IgG autoantibody production by purified splenic CD19(+) B cells. Whereas invariant NKT cells secreted large amounts of IL-17 and IL-21, and helped B cells, non-NKT cells did not. The subset of IL-17 secreting NZB/W NKT cells expressed the Ly108(lo)CD4(-)NK1.1(-) phenotype, whereas the IL-21 secreting subset expressed the Ly108(hi)CD4(+)NK1.1(-) phenotype and helped B cells secrete a variety of IgG anti-nuclear antibodies. α-galactocylceramide enhanced the helper activity of NZB/W and B6.Sle1b NKT cells for IgG autoantibody secretion by syngeneic B cells. In conclusion, different subsets of iNKT cells from mice with genetic susceptibility to lupus can contribute to pathogenesis by secreting pro-inflammatory cytokines and helping autoantibody production.

    View details for DOI 10.1016/j.jaut.2014.01.002

    View details for PubMedID 24508410

    View details for PubMedCentralID PMC4002579

  • Path to clinical transplantation tolerance and prevention of graft versus host disease. Immunologic Research Strober, S. 2014; 58 (2-3): 240-8
  • Requirement for interactions of natural killer T cells and myeloid derived suppressor cells for transplantation tolerance AJT Hongo, D., Tang, X., Baker, J., Engleman, E. G., Strober, s. 2014; 14 (11): 2467-77
  • Treatment of 4T1 metastatic breast cancer tumors with combined hypofractionated radiation and autologous T cell transplantation infusion Radiation Research Filatenkov, A., Baker, J., Ahn, G. O., Kohrt, H., Dutt, S., Dejbakhsh-Jones, S., Negrin, R. S., Engleman, E. G., Strober, S. 2014; 182 (2): 163-169
  • Chimerism, graft survival, and withdrawal of immunosupressive drugs in HLA matched and mismatched patients after kidney and hematopoietic cell transplantation AJT Scandling, J. D., Busque, S., Shizuru, J. A., Lowsky, R., Hoppe, R., Dejbakhsh-Jones, S., Jensen, K., Shori, A., Strober, J. A., Lavori, P., Turnbull, B. B., Engleman, E. G., Strober, S. 2014
  • Ly108 expression distinguishes subsets of invariant NKT cells that help autoantibody production and secrete IL-21 from those that secrete IL-17 in lupus prone NZB/W mice J Autoimmun Tang, X., Jarrell, J. A., Price, J. V., Dai, H., Utz, P. J., Strober, S. 2014; 50: 87-98
  • Identification of gene microarray expression profiles in patients with chronic graft-versus-host disease following allogeneic hematopoietic cell transplantation. Clinical immunology Kohrt, H. E., Tian, L., Li, L., Alizadeh, A. A., Hsieh, S., Tibshirani, R. J., Strober, S., Sarwal, M., Lowsky, R. 2013; 148 (1): 124-135

    Abstract

    Chronic graft-versus-host disease (GVHD) results in significant morbidity and mortality, limiting the benefit of allogeneic hematopoietic cell transplantation (HCT). Peripheral blood gene expression profiling of the donor immune repertoire following HCT may provide associated genes and pathways thereby improving the pathophysiologic understanding of chronic GVHD. We profiled 70 patients and identified candidate genes that provided mechanistic insight in the biologic pathways that underlie chronic GVHD. Our data revealed that the dominant gene signature in patients with chronic GVHD represented compensatory responses that control inflammation and included the interleukin-1 decoy receptor, IL-1 receptor type II, and genes that were profibrotic and associated with the IL-4, IL-6 and IL-10 signaling pathways. In addition, we identified three genes that were important regulators of extracellular matrix. Validation of this discovery phase study will determine if the identified genes have diagnostic, prognostic or therapeutic implications.

    View details for DOI 10.1016/j.clim.2013.04.013

    View details for PubMedID 23685278

  • Characterization of direct radiation-induced immune function and molecular signaling changes in an antigen presenting cell line CLINICAL IMMUNOLOGY Parker, J. J., Jones, J. C., Strober, S., Knox, S. J. 2013; 148 (1): 44-55

    Abstract

    Radiation therapy is a widely used cancer treatment and pre-transplantation conditioning regimen that has the potential to influence anti-tumor and post-transplantation immune responses. Although conventionally fractionated radiation doses can suppress immune responses by depleting lymphocytes, single high doses of local tumor radiation can enhance immune responses. Using phospho-flow cytometry analysis of a human monocytic cell line, we identified novel radiation-induced changes in the phosphorylation state of NFκB family members known in other cell types to maintain and regulate immune function. These phosphorylation changes were p53 independent, but were strongly dependent upon ATM activation due to DNA damage. We found that radiation promotes the activation and APC functional maturation through phosphorylation of NFκB Essential Modulator (NEMO). Our results and the analytic methods are especially well suited to the study of functional changes in APC when radiation is used for immune modulation in clinical protocols.

    View details for DOI 10.1016/j.clim.2013.03.008

    View details for Web of Science ID 000320427300006

    View details for PubMedID 23649044

  • A distinct evolution of the T-cell repertoire categorizes treatment refractory gastrointestinal acute graft-versus-host disease BLOOD Meyer, E. H., Hsu, A. R., Liliental, J., Loehr, A., Florek, M., Zehnder, J. L., Strober, S., Lavori, P., Miklos, D. B., Johnson, D. S., Negrin, R. S. 2013; 121 (24): 4955-4962

    Abstract

    Steroid refractory gastrointestinal (GI) acute graft versus host disease (aGVHD) is a major cause of mortality in hematopoietic stem cell transplantation (HCT) without immune markers to establish a diagnosis or guide therapy. We found that T cell receptor β (TCRβ) CDR3 repertoire sequencing reveals patterns that could eventually serve as a disease biomarker of T cell alloreactivity in aGVHD. We identified T cell clones in GI biopsies in a heterogeneous group of 15 allogeneic HCT patients with GI aGVHD symptoms. Seven steroid-refractory aGVHD patients showed a more conserved TCRβ clonal structure between different biopsy sites in the GI tract than eight primary-therapy responsive patients. Tracking GI clones identified at endoscopy longitudinally in the blood also revealed an increased clonal expansion in patients with steroid-refractory disease. Immune repertoire sequencing-based methods could enable a novel personalized way to guide diagnosis and therapy in diseases where T cell activity is a major determinant.

    View details for DOI 10.1182/blood-2013-03-489757

    View details for Web of Science ID 000321896300024

  • Uniform Long-Term Graft Survival in a Clincial Trial of the Induction of Tolerance to Kidney Transplants. 13th American Transplant Congress (ATC) Scandling, J., Busque, S., Shori, A., Dejbakhsh-Jones, S., Shizuru, J., Lowsky, R., Benike, C., Engleman, E., Strober, S. WILEY-BLACKWELL. 2013: 200–200
  • The Expansion of Gastrointestinal-Associated alpha beta T Cell Clones in Peripheral Blood Associates with Severe Steroid Refractory GVHD BMT Tandem Meetings Meyer, E. H., Liliental, J. A., Florek, M., Lohr, A., Hsu, A., Johnson, D., Lavori, P., Zehnder, J. L., Miklos, D. B., Strober, S., Negrin, R. ELSEVIER SCIENCE INC. 2013: S334–S335
  • Outcomes After Non-Myeloablative Allogeneic Hematopoietic Cell Transplantation with Total Lymphoid Irradiation and Anti-Thymocyte Globulin in Lymphoid Malignancies After Failed Autologous Transplantation BMT Tandem Meetings Kanate, A. S., Efron, B., Chhabra, S., Kohrt, H., Shizuru, J. A., Laport, G. G., Miklos, D. B., Benjamin, J., Johnston, L., Arai, S., Weng, W., Negrin, R., Strober, S., Lowsky, R. ELSEVIER SCIENCE INC. 2013: S154–S155
  • A distinct evolution of the T-cell repertoire categorizes treatment refractory gastrointestinal acute graft-versus-disease Blood Meyer, E. H., Hsu, A. R., Liliental, J., Lohr, A., Zehnder, M., Strober, S., Lavori, P., Miklos, D. B., Johnson, D. S., Negrin, R. S. 2013; 121 (24): 4955-4962
  • A Decade'S Experience with Safety and Efficacy of Tolerance Induction in Clinical Kidney Transplantation Scandling, J. D., Busque, S., Dejbakhsh-Jones, S., Benike, C., Shori, A., Shizuru, J., Lowsky, R., Engleman, E., Strober, S. LIPPINCOTT WILLIAMS & WILKINS. 2012: 55
  • Identification of Candidate Transcriptional Biomarkers Associated with Chronic Graft-Versus-Host Disease Following Allogeneic Hematopoietic Cell Transplantation 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Kohrt, H. E., Tian, L., Li, L., Alizadeh, A. A., Hsieh, S., Strober, S., Sarwal, M., Lowsky, R. AMER SOC HEMATOLOGY. 2012
  • Identification of Candidate Transcriptional Biomarkers Associated with Chronic Graft-Versus-Host Disease Following Allogeneic Hematopoietic Cell Transplantation Kohrt, H. E., Tian, L., Li, L., Alizadeh, A. A., Hsieh, S., Strober, S., Sarwal, M., Lowsky, R. AMER SOC HEMATOLOGY. 2012
  • Rare cells predict GVHD. Blood Strober, S., Lowsky, R. 2012; 119 (21): 4820-4821

    View details for DOI 10.1182/blood-2012-04-417311

    View details for PubMedID 22627595

  • Tolerance and Withdrawal of Immunosuppressive Drugs in Patients Given Kidney and Hematopoietic Cell Transplants AMERICAN JOURNAL OF TRANSPLANTATION Scandling, J. D., Busque, S., Dejbakhsh-Jones, S., Benike, C., Sarwal, M., Millan, M. T., Shizuru, J. A., Lowsky, R., Engleman, E. G., Strober, S. 2012; 12 (5): 1133-1145

    Abstract

    Sixteen patients conditioned with total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) were given kidney transplants and an injection of CD34+ hematopoietic progenitor cells and T cells from HLA-matched donors in a tolerance induction protocol. Blood cell monitoring included changes in chimerism, balance of T-cell subsets and responses to donor alloantigens. Fifteen patients developed multilineage chimerism without graft-versus-host disease (GVHD), and eight with chimerism for at least 6 months were withdrawn from antirejection medications for 1-3 years (mean, 28 months) without subsequent rejection episodes. Four chimeric patients have just completed or are in the midst of drug withdrawal, and four patients were not withdrawn due to return of underlying disease or rejection episodes. Blood cells from all patients showed early high ratios of CD4+CD25+ regulatory T cells and NKT cells versus conventional naive CD4+ T cells, and those off drugs showed specific unresponsiveness to donor alloantigens. In conclusion, TLI and ATG promoted the development of persistent chimerism and tolerance in a cohort of patients given kidney transplants and hematopoietic donor cell infusions. All 16 patients had excellent graft function at the last observation point with or without maintenance drugs.

    View details for DOI 10.1111/j.1600-6143.2012.03992.x

    View details for Web of Science ID 000303235100012

    View details for PubMedID 22405058

    View details for PubMedCentralID PMC3338901

  • Gene Array Pattern for Induced Human Kidney Transplant Tolerance with Safe Immunosuppression Withdrawal Li, L., Hsieh, S., Lowsky, R., Busque, S., Scandling, J., Jones, S., Strober, S., Sarwal, M. WILEY-BLACKWELL. 2012: 183
  • Interactions between NKT cells and Tregs are required for tolerance to combined bone marrow and organ transplants BLOOD Hongo, D., Tang, X., Dutt, S., Nador, R. G., Strober, S. 2012; 119 (6): 1581-1589

    Abstract

    We used a model of combined bone marrow and heart transplantation, in which tolerance and stable chimerism is induced after conditioning with fractionated irradiation of the lymphoid tissues and anti-T-cell antibodies. Graft acceptance and chimerism required host CD4(+)CD25(+) Treg production of IL-10 that was in-turn enhanced by host invariant natural killer (NK) T-cell production of IL-4. Up-regulation of PD-1 on host Tregs, CD4(+)CD25(-) conventional T (Tcon) cells, and CD8(+) T cells was also enhanced by NKT cell production of IL-4. Up-regulated PD-1 expression on Tregs was linked to IL-10 secretion, on CD8(+) T cells was linked to Tim-3 expression, and on CD4(+) Tcon cells was associated with reduced IFNγ secretion. Changes in the expression of PD-1 were induced by the conditioning regimen, and declined after bone marrow transplantation. In conclusion, NKT cells in this model promoted changes in expression of negative costimulatory receptors and anti-inflammatory cytokines by Tregs and other T-cell subsets in an IL-4-dependent manner that resulted in tolerance to the bone marrow and organ grafts.

    View details for DOI 10.1182/blood-2011-08-371948

    View details for Web of Science ID 000300420900035

    View details for PubMedID 22174155

    View details for PubMedCentralID PMC3286219

  • Donor Immunization with WT1 Peptide Augments Anti-Leukemic Activity After MHC-Matched Bone Marrow Transplantation 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Kohrt, H. E., Mueller, A. M., Baker, J. B., Goldstein, M. J., Newell, E., Dutt, S., Czerwinski, D. K., Lowsky, R., Strober, S. AMER SOC HEMATOLOGY. 2011: 827–28
  • Donor immunization with WT1 peptide augments antileukemic activity after MHC-matched bone marrow transplantation. Blood Kohrt, H. E., Müller, A., Baker, J., Goldstein, M. J., Newell, E., Dutt, S., Czerwinski, D., Lowsky, R., Strober, S. 2011; 118 (19): 5319-5329

    Abstract

    The curative potential of MHC-matched allogeneic bone marrow transplantation (BMT) is in part because of immunologic graft-versus-tumor (GvT) reactions mediated by donor T cells that recognize host minor histocompatibility antigens. Immunization with leukemia-associated antigens, such as Wilms Tumor 1 (WT1) peptides, induces a T-cell population that is tumor antigen specific. We determined whether allogeneic BMT combined with immunotherapy using WT1 peptide vaccination of donors induced more potent antitumor activity than either therapy alone. WT1 peptide vaccinations of healthy donor mice induced CD8(+) T cells that were specifically reactive to WT1-expressing FBL3 leukemia cells. We found that peptide immunization was effective as a prophylactic vaccination before tumor challenge, yet was ineffective as a therapeutic vaccination in tumor-bearing mice. BMT from vaccinated healthy MHC-matched donors, but not syngeneic donors, into recipient tumor-bearing mice was effective as a therapeutic maneuver and resulted in eradication of FBL3 leukemia. The transfer of total CD8(+) T cells from immunized donors was more effective than the transfer of WT1-tetramer(+)CD8(+) T cells and both required CD4(+) T-cell help for maximal antitumor activity. These findings show that WT1 peptide vaccination of donor mice can dramatically enhance GvT activity after MHC-matched allogeneic BMT.

    View details for DOI 10.1182/blood-2011-05-356238

    View details for PubMedID 21868578

    View details for PubMedCentralID PMC3217412

  • Donor immunization with WT1 peptide augments antileukemic activity after MHC-matched bone marrow transplantation BLOOD Kohrt, H. E., Mueller, A., Baker, J., Goldstein, M. J., Newell, E., Dutt, S., Czerwinski, D., Lowsky, R., Strober, S. 2011; 118 (19): 5319-5329
  • Selective Resistance of CD44(hi) T Cells to p53-Dependent Cell Death Results in Persistence of Immunologic Memory after Total Body Irradiation JOURNAL OF IMMUNOLOGY Yao, Z., Jones, J., Kohrt, H., Strober, S. 2011; 187 (8): 4100-4108

    Abstract

    Our previous studies showed that treatment of mice with total body irradiation (TBI) or total lymphoid tissue irradiation markedly changes the balance of residual T cell subsets to favor CD4(+)CD44(hi) NKT cells because of the differential resistance of the latter subset to cell death. The object of the current study was to further elucidate the changed balance and mechanisms of differential radioresistance of T cell subsets after graded doses of TBI. The experimental results showed that CD4(+) T cells were markedly more resistant than CD8(+) T cells, and CD44(hi) T cells, including NKT cells and memory T cells, were markedly more resistant than CD44(lo) (naive) T cells. The memory T cells immunized to alloantigens persisted even after myeloablative (1000 cGy) TBI and were able to prevent engraftment of bone marrow transplants. Although T cell death after 1000 cGy was prevented in p53(-/-) mice, there was progressive T cell death in p53(-/-) mice at higher doses. Although p53-dependent T cell death changed the balance of subsets, p53-independent T cell death did not. In conclusion, resistance of CD44(hi) T cells to p53-dependent cell death results in the persistence of immunological memory after TBI and can explain the immune-mediated rejection of marrow transplants in sensitized recipients.

    View details for DOI 10.4049/jimmunol.1101141

    View details for PubMedID 21930972

    View details for PubMedCentralID PMC3186844

  • Translational studies in hematopoietic cell transplantation: Treatment of hematologic malignancies as a stepping stone to tolerance induction SEMINARS IN IMMUNOLOGY Strober, S., Spitzer, T. R., Lowsky, R., Sykes, M. 2011; 23 (4): 273-281

    Abstract

    Allogeneic hematopoietic cell transplantation (HCT) has most commonly been used to treat hematologic malignancies, where it is often the only potentially curative option available. The success of HCT has been limited by transplant-associated toxicities related to the conditioning regimens used and to the common immunologic consequence of donor T cell recognition of recipient alloantigens, graft-vs-host disease (GVHD). The frequency and severity of GVHD observed when extensive HLA barriers are transgressed has essentially precluded the routine use of extensively HLA-mismatched HCT. Allogeneic HCT also has potential as an approach to organ allograft tolerance induction, but this potential has not been previously realized because of the toxicity associated with traditional conditioning. In this paper we review two approaches to HCT involving reduced intensity conditioning regimens that have been associated with improvements in safety in patients with hematologic malignancies, even in the HLA-mismatched transplant setting. These strategies have been applied in the first successful pilot studies for the induction of organ allograft tolerance in humans. Thus, we summarize an example of vertical translational research between animal models and humans and horizontal translation between two separate goals that culminated in the use of HCT to achieve allograft tolerance in humans.

    View details for DOI 10.1016/j.smim.2011.05.001

    View details for Web of Science ID 000296403800006

    View details for PubMedID 21705229

    View details for PubMedCentralID PMC3201788

  • Changes in T Cell Subsets in 12 Patients Enrolled in a Tolerance Induction Protocol with Combined Kidney and Hematopoietic Cell Transplantation. American Transplant Congress Dejbakhsh-Jones, S., Takahashi, K., Jensen, K. P., Busque, S., Scandling, J. D., Shizuru, J., Lowsky, R., Engleman, E., Strober, S. WILEY-BLACKWELL. 2011: 177–177
  • NKT cells in lupus prone NZB/W mice are abnormal and expression of Ly108 (SLAMF6) affects proinflammatory cytokine secretion and help for autoreactive B cells Tang, X., Strober, S. AMER ASSOC IMMUNOLOGISTS. 2011
  • Changes in T cell subsets in 12 patients enrolled in a tolerance induction protocol with combined kidney and hematopoietic cell transplantation Dejbakhsh-Jones, S., Takahashi, K., Jensen, K., Busgue, S., Scandling, J., Shizuru, J., Lowsky, R., Engleman, E., Strober, S. AMER ASSOC IMMUNOLOGISTS. 2011
  • CD8(+)CD44(hi) but not CD4(+)CD44(hi) memory T cells mediate potent graft antilymphoma activity without GVHD BLOOD Dutt, S., Baker, J., Kohrt, H. E., Kambham, N., Sanyal, M., Negrin, R. S., Strober, S. 2011; 117 (11): 3230-3239

    Abstract

    Allogeneic hematopoietic cell transplantation can be curative in patients with leukemia and lymphoma. However, progressive growth of malignant cells, relapse after transplantation, and graft-versus-host disease (GVHD) remain important problems. The goal of the current murine study was to select a freshly isolated donor T-cell subset for infusion that separates antilymphoma activity from GVHD, and to determine whether the selected subset could effectively prevent or treat progressive growth of a naturally occurring B-cell lymphoma (BCL(1)) without GVHD after recipients were given T cell-depleted bone marrow transplantations from major histocompatibility complex-mismatched donors. Lethal GVHD was observed when total T cells, naive CD4(+) T cells, or naive CD8(+) T cells were used. Memory CD4(+)CD44(hi) and CD8(+)CD44(hi) T cells containing both central and effector memory cells did not induce lethal GVHD, but only memory CD8(+) T cells had potent antilymphoma activity and promoted complete chimerism. Infusion of CD8(+) memory T cells after transplantation was able to eradicate the BCL(1) lymphoma even after progressive growth without inducing severe GVHD. In conclusion, the memory CD8(+) T-cell subset separated graft antilymphoma activity from GVHD more effectively than naive T cells, memory CD4(+) T cells, or memory total T cells.

    View details for DOI 10.1182/blood-2010-10-312751

    View details for PubMedID 21239702

  • NONINVASIVE PREDICTION OF GRAFT-VERUS-HOST DISEASE FOLLOWING ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION BY GENE EXPRESSION PROFILING Kohrt, H. E., Li, L., Alizadeh, A. A., Heish, S., Goldstein, M. J., Strober, S., Sarwal, M., Lowsky, R. ELSEVIER SCIENCE INC. 2011: S336
  • IMMUNOMAGNETIC SELECTION OF CD8+MEMORY CELLS FOR THERAPEUTIC APPLICATIONS Armstrong, R., Lowsky, R., Strober, S., Sheehan, K. ELSEVIER SCIENCE INC. 2011: S220
  • Noninvasive Prediction of Graft-Verus-Host Disease Following Allogeneic Hematopoietic Cell Transplantation by Gene Expression Profiling 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Kohrt, H. E., Li, L., Alizadeh, A. A., Goldstein, M. J., Strober, S., Sarwal, M., Lowsky, R. AMER SOC HEMATOLOGY. 2010: 393–94
  • Complete immunosuppressive drug withdrawal from liver transplant recipients conditioned with total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) Annual Clinical Congress of American-College-of-Surgeons Gallo, A., Strober, S., Concepcion, W., Esquivel, C. ELSEVIER SCIENCE INC. 2010: S64–S64
  • NKT cells, Treg, and their interactions in bone marrow transplantation EUROPEAN JOURNAL OF IMMUNOLOGY Kohrt, H. E., Pillai, A. B., Lowsky, R., Strober, S. 2010; 40 (7): 1862-1869

    Abstract

    Bone marrow transplantation (BMT) is a potentially curative treatment for patients with leukemia and lymphoma. Tumor eradication is promoted by the anti-tumor activity of donor T cells contained in the transplant; however, donor T cells also mediate the serious side effect of graft-versus-host disease (GVHD). Separation of GVHD from graft anti-tumor activity is an important goal of research in improving transplant outcome. One approach is to take advantage of the immunomodulatory activity of regulatory NKT cells and CD4(+)CD25(+) Treg of host and/or donor origin. Both host and donor NKT cells and donor Treg are able to prevent GVHD in murine models. In this review, we summarize the mechanisms of NKT cell- and Treg-mediated protection against GVHD in mice while maintaining graft anti-tumor activity. In addition, we also examine the interactions between NKT cells and Treg in the context of BMT, and integrate the data from murine experimental models with the observations made in humans.

    View details for DOI 10.1002/eji.201040394

    View details for Web of Science ID 000280220600014

    View details for PubMedID 20583031

    View details for PubMedCentralID PMC2926162

  • Noninvasive Prediction of Graft-Versus-Host Disease Following Allogeneic Hematopoietic Cell Transplantation by Gene Expression Profiling. 10th American Transplant Congress Li, L., Kohrt, H., Heish, S., Alizadeh, A., Laport, G., Shizuru, J., Negrin, R., Strober, S., Lowsky, R., Sarwal, M. WILEY-BLACKWELL. 2010: 483–483
  • Inducing Immune Tolerance in Clinical Kidney Transplantation Scandling, J., Busque, S., Dejbakhsh-Jones, S., Benike, C., Li, L., Holmes, T., Shizuru, J., Lowsky, R., Engleman, E., Sarwal, M., Strober, S. WILEY-BLACKWELL PUBLISHING, INC. 2010: 139
  • Induction of Immune Tolerance and Chimerism after Renal and Hematopoietic Cell Transplantation in Humans. Dejbakhsh-Jones, S., Scanding, J., Busque, S., Benike, C., Mukhopadhyay, A., Engleman, E., Strober, S. WILEY-BLACKWELL PUBLISHING, INC. 2010: 140–41
  • Induced Tolerance to Rat Liver Allografts Involves the Apoptosis of Intragraft T Cells and the Generation of CD4(+)CD25(+)FoxP3(+) T Regulatory Cells LIVER TRANSPLANTATION Fujiki, M., Esquivel, C. O., Martinez, O. M., Strober, S., Uemoto, S., Krams, S. M. 2010; 16 (2): 147-154

    Abstract

    Posttransplant total lymphoid irradiation is a nonmyeloablative regimen that has been extensively studied in rodent models for the induction of tolerance to bone marrow and solid organ allografts. Previous studies of experimental models and clinical transplantation have used total lymphoid irradiation in combination with anti-lymphocyte-depleting reagents and donor cell infusion to promote graft acceptance. In a rat model of orthotopic liver transplantation, we demonstrated that total lymphoid irradiation alone induced long-term graft survival. Apoptotic T cells were detected in markedly higher numbers in the livers of the total lymphoid irradiation-treated group in comparison with the control group of liver allograft recipients. Intragraft CD4(+)CD25(+)FoxP3(+) cells were increased in the total lymphoid irradiation group in the first week post-transplant and remained elevated in the graft and in the spleen. Importantly, the adoptive transfer of splenocytes from recipients that received posttransplant total lymphoid irradiation prolonged the survival of donor heart grafts, but not third-party heart grafts, whereas the depletion of CD4(+)CD25(+) cells from transferred splenocytes abrogated this prolongation. We conclude that posttransplant total lymphoid irradiation significantly increases the apoptosis of T cells in the liver graft and allows the accumulation of CD4(+)CD25(+)FoxP3(+) T regulatory cells, which facilitate the generation of donor-specific tolerance.

    View details for DOI 10.1002/lt.21963

    View details for Web of Science ID 000274437800005

    View details for PubMedID 20104482

    View details for PubMedCentralID PMC2937179

  • The Changed Balance of Regulatory and Naive T Cells Promotes Tolerance after TLI and Anti-T-Cell Antibody Conditioning AMERICAN JOURNAL OF TRANSPLANTATION Nador, R. G., Hongo, D., Baker, J., Yao, Z., Strober, S. 2010; 10 (2): 262-272

    Abstract

    The goal of the study was to determine how the changed balance of host naïve and regulatory T cells observed after conditioning with total lymphoid irradiation (TLI) and antithymocyte serum (ATS) promotes tolerance to combined organ and bone marrow transplants. Although previous studies showed that tolerance was dependent on host natural killer T (NKT) cells, this study shows that there is an additional dependence on host CD4(+)CD25(+) Treg cells. Depletion of the latter cells before conditioning resulted in rapid rejection of bone marrow and organ allografts. The balance of T-cell subsets changed after TLI and ATS with TLI favoring mainly NKT cells and ATS favoring mainly Treg cells. Combined modalities reduced the conventional naïve CD4(+) T cells 2800-fold. The host type Treg cells that persisted in the stable chimeras had the capacity to suppress alloreactivity to both donor and third party cells in the mixed leukocyte reaction. In conclusion, tolerance induction after conditioning in this model depends upon the ability of naturally occurring regulatory NKT and Treg cells to suppress the residual alloreactive T cells that are capable of rejecting grafts.

    View details for DOI 10.1111/j.1600-6143.2009.02942.x

    View details for Web of Science ID 000273884800015

    View details for PubMedID 20041865

    View details for PubMedCentralID PMC2886014

  • Gene Arrays May Predict Stable Clinical Kidney Tolerance and Support Safe Immunosuppression Withdrawal American-Society-of-Transplantation Annual Scientific Exchange Sarwal, M. M., Li, L., Hsieh, S., Lowsky, R., Busque, S., Scandling, J., Jones, S., Strober, S. WILEY-BLACKWELL PUBLISHING, INC. 2010: 1–1
  • Inducing Tolerance in Clinical Kidney Transplantation Scandling, J., Busque, S., Dejbakhsh-Jones, S., Benike, C., Li, L., Holmes, T., Shizuru, J., Lowsky, R., Engleman, E., Sarwal, M., Strober, S. WILEY-BLACKWELL PUBLISHING, INC. 2010: 1
  • Changes in T Cell Subsets in Patients with Tolerance and Chimerism after Renal and Hematopoietic Cell Transplantation Dejbakhsh-Jones, S., Scanding, J., Busque, S., Benike, C., Mukhopadhyay, A., Engleman, E., Strober, S. WILEY-BLACKWELL PUBLISHING, INC. 2010: 18
  • Ineffective Vaccination against Solid Tumors Can Be Enhanced by Hematopoietic Cell Transplantation JOURNAL OF IMMUNOLOGY Filatenkov, A., Mueller, A. M., Tseng, W. W., Dejbakhsh-Jones, S., Winer, D., Luong, R., Shizuru, J. A., Engleman, E. G., Strober, S. 2009; 183 (11): 7196-7203

    Abstract

    Vaccination with tumor Ags has not been an effective treatment for solid tumors. The goal of the current study was to determine whether a combination of vaccination and hematopoietic cell transplantation (HCT) can effectively treat primary, disseminated, or metastatic CT26 and MC38 murine colon tumors. Vaccination of tumor-bearing mice with irradiated tumor cells and CpG adjuvant failed to alter progressive tumor growth. However, mice bearing primary, disseminated lung, or metastatic liver tumors were uniformly cured after administration of total body irradiation, followed by the transplantation of hematopoietic progenitor cells and T cells from syngeneic, but not allogeneic vaccinated donors. Requirements for effective treatment of tumors included irradiation of hosts, vaccination of donors with both tumor cells and CpG, transfer of both CD4(+) and CD8(+) T cells along with progenitor cells, and ability of donor cells to produce IFN-gamma. Irradiation markedly increased the infiltration of donor T cells into the tumors, and the combined irradiation and HCT altered the balance of tumor-infiltrating cells to favor CD8(+) effector memory T cells as compared with CD4(+)CD25(+)FoxP3(+) T regulatory cells. The combination of vaccination and autologous hematopoietic cell transplantation was also effective in treating tumors. In conclusion, these findings show that otherwise ineffective vaccination to solid nonhematologic tumors can be dramatically enhanced by HCT.

    View details for DOI 10.4049/jimmunol.0900159

    View details for Web of Science ID 000272478800039

    View details for PubMedID 19890041

    View details for PubMedCentralID PMC2783632

  • Memory Phenotype CD8+T Cells Are Superior to Naive CD8+T Cells in Separating Graft Anti-Tumor Activity From Gvhd After Bone Marrow Transplantation; Application to DLI. Dutt, S., Baker, J., Kambham, N., Kohrt, H. E., Negrin, R., Strober, S. AMER SOC HEMATOLOGY. 2009: 967
  • beta-galactosylceramide alters invariant natural killer T cell function and is effective treatment for lupus CLINICAL IMMUNOLOGY Morshed, S. R., Takahashi, T., Savage, P. B., Kambham, N., Strober, S. 2009; 132 (3): 321-333

    Abstract

    NZB/W female mice spontaneously develop systemic lupus, an autoantibody mediated disease associated with immune complex glomerulonephritis. Natural killer (NK) T cells augment anti-dsDNA antibody secretion by NZB/W B cells in vitro, and blocking NKT cell activation in vivo with anti-CD1 mAb ameliorates lupus disease activity. In the current study, we show that beta-galactosylceramide reduces the in vivo induction of serum IFN-gamma and/or IL-4 by the potent NKT cell agonist alpha-galactosylceramide and reduces NKT cell helper activity for IgG secretion. Treatment of NZB/W mice with the beta-galactosylceramide ameliorated lupus disease activity as judged by improvement in proteinuria, renal histopathology, IgG anti-dsDNA antibody formation, and survival. In conclusion, beta-galactosylceramide, a glycolipid that reduces the cytokine secretion induced by a potent NKT cell agonist ameliorates lupus in NZB/W mice.

    View details for DOI 10.1016/j.clim.2009.05.018

    View details for Web of Science ID 000268783900004

    View details for PubMedID 19564135

    View details for PubMedCentralID PMC2720447

  • TLI and ATG conditioning with low risk of graft-versus-host disease retains antitumor reactions after allogeneic hematopoietic cell transplantation from related and unrelated donors BLOOD Kohrt, H. E., Turnbull, B. B., Heydari, K., Shizuru, J. A., Laport, G. G., Miklos, D. B., Johnston, L. J., Arai, S., Weng, W., Hoppe, R. T., Lavori, P. W., Blume, K. G., Negrin, R. S., Strober, S., Lowsky, R. 2009; 114 (5): 1099-1109

    Abstract

    A hematopoietic cell transplantation regimen was adapted from a preclinical model that used reduced-intensity conditioning (RIC) and protected against graft-versus-host disease (GVHD) by skewing residual host T-cell subsets to favor regulatory natural killer T cells. One hundred eleven patients with lymphoid (64) and myeloid (47) malignancies received RIC using total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) followed by the infusion of granulocyte colony-stimulating factor-mobilized grafts. Included were 34 patients at least 60 years of age, 32 patients at high risk of lymphoma relapse after disease recurrence following prior autologous transplantation, and 51 patients at high risk of developing GVHD due to lack of a fully human leukocyte antigen (HLA)-matched related donor. Durable chimerism was achieved in 97% of patients. Cumulative probabilities of acute GVHD (grades II-IV) were 2 and 10% of patients receiving related and unrelated donor grafts. Nonrelapse mortality (NRM) at 1 year was less than 4%. Cumulative incidence of chronic GVHD was 27%. The 36-month probability of overall and event-free survival was 60% and 40%, respectively. Disease status at start of conditioning and the level of chimerism achieved after transplantation significantly impacted clinical outcome. The high incidence of sustained remission among patients with active disease at time of transplantation suggests retained graft-versus-tumor reactions. Active trial registration currently at clinicaltrials.gov under IDs of NCT00185640 and NCT00186615.

    View details for DOI 10.1182/blood-2009-03-211441

    View details for PubMedID 19423725

  • Host natural killer T cells induce an interleukin-4-dependent expansion of donor CD4(+)CD25(+)Foxp3(+) T regulatory cells that protects against graft-versus-host disease 48th Annual Meeting of the American-Society-of-Hematology Pillai, A. B., George, T. I., Dutt, S., Strober, S. AMER SOC HEMATOLOGY. 2009: 4458–67

    Abstract

    Although CD4(+)CD25(+) T cells (T regulatory cells [Tregs]) and natural killer T cells (NKT cells) each protect against graft-versus-host disease (GVHD), interactions between these 2 regulatory cell populations after allogeneic bone marrow transplantation (BMT) have not been studied. We show that host NKT cells can induce an in vivo expansion of donor Tregs that prevents lethal GVHD in mice after conditioning with fractionated lymphoid irradiation (TLI) and anti-T-cell antibodies, a regimen that models human GVHD-protective nonmyeloablative protocols using TLI and antithymocyte globulin (ATG), followed by allogeneic hematopoietic cell transplantation (HCT). GVHD protection was lost in NKT-cell-deficient Jalpha18(-/-) hosts and interleukin-4 (IL-4)(-/-) hosts, or when the donor transplant was Treg depleted. Add-back of donor Tregs or wild-type host NKT cells restored GVHD protection. Donor Treg proliferation was lost in IL-4(-/-) hosts or when IL-4(-/-) mice were used as the source of NKT cells for adoptive transfer, indicating that host NKT cell augmentation of donor Treg proliferation after TLI/antithymocyte serum is IL-4 dependent. Our results demonstrate that host NKT cells and donor Tregs can act synergistically after BMT, and provide a mechanism by which strategies designed to preserve host regulatory cells can augment in vivo donor Treg expansion to regulate GVHD after allogeneic HCT.

    View details for DOI 10.1182/blood-2008-06-165506

    View details for PubMedID 19221040

  • Induced Tolerance to Liver Allografts Involves Apoptosis and the Generation of Regulatory T Cells Fujiki, M., Esquivel, C. O., Martinez, O. M., Strober, S., Krams, S. M. AMER ASSOC IMMUNOLOGISTS. 2009
  • Differences in Bcl-2 Expression by T Cell Subsets Alter Their Balance After In Vivo Irradiation to Favor Regulatory NKT Cells and CD4(+) CD25(+) T Cells in Wild Type But Not p53(-/-) Mice Yao, Z., Jones, J., Liu, Y., Strober, S. AMER ASSOC IMMUNOLOGISTS. 2009
  • Differences in Bcl-2 expression by T-cell subsets alter their balance after in vivo irradiation to favor CD4+Bcl-2(hi) NKT cells EUROPEAN JOURNAL OF IMMUNOLOGY Yao, Z., Liu, Y., Jones, J., Strober, S. 2009; 39 (3): 763-775

    Abstract

    Although it is well known that in vivo radiation depletes immune cells via the Bcl-2 apoptotic pathway, a more nuanced analysis of the changes in the balance of immune-cell subsets is needed to understand the impact of radiation on immune function. We show the balance of T-cell subsets changes after increasing single doses of total body irradiation (TBI) or after fractionated irradiation of the lymphoid tissues (TLI) of mice due to differences in radioresistance and Bcl-2 expression of the NKT-cell and non-NKT subsets to favor CD4(+)Bcl-2(hi) NKT cells. Reduction of the Bcl-2(lo) mature T-cell subsets was at least 100-fold greater than that of the Bcl-2(hi) subsets. CD4(+) NKT cells upregulated Bcl-2 after TBI and TLI and developed a Th2 bias after TLI, whereas non-NKT cells failed to do so. Our previous studies showed TLI protects against graft versus host disease in wild-type, but not in NKT-cell-deficient mice. The present study shows that NKT cells have a protective function even after TBI, and these cells are tenfold more abundant after an equal dose of TLI. In conclusion, differential expression of Bcl-2 contributes to the changes in T-cell subsets and immune function after irradiation.

    View details for DOI 10.1002/eji.200838657

    View details for Web of Science ID 000264683500025

    View details for PubMedID 19197937

    View details for PubMedCentralID PMC2758339

  • HOST NATURAL KILLER T CELLS INDUCE AN IL-4 DEPENDENT EXPANSION OF DONOR CD4(+)CD25(+)FOXP3(+) TREGS THAT PROTECTS AGAINST LETHAL ACUTE GRAFT-VERSUS-HOST DISEASE Pillai, A. B., George, T., Dutt, S., Strober, S. ELSEVIER SCIENCE INC. 2009: 14
  • Gene Arrays May Predict Stable Clinical Tolerance and Support Safe Immunosuppression Withdrawal. 9th Joint Meeting of the American-Society-of-Transplant-Surgeon/American-Society-of-Transplantation Sarwal, M. M., Li, L., Hsieh, S., Lowsky, R., Busque, S., Scandling, J., Jones, S., Strober, S. WILEY-BLACKWELL. 2009: 280–280
  • Induced Tolerance to Liver Allografts Involves Apoptosis and the Generation of Regulatory T Cells Fujiki, M., Strober, S., Martinez, O., Esquivel, C., Krams, S. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2009: S76
  • Changes in T Cell Subsets after TLI/ATG Conditioning That Promotes Tolerance to Combined Kidney and Hematopoietic Cell Transplants in Human. Dejbakhsh-Jones, S., Scanding, J., Busque, S., Nador, R., Hongo, D., Benike, C., Mukhopadhyay, A., Engleman, E., Strober, S. WILEY-BLACKWELL PUBLISHING, INC. 2009: 281
  • Changes in T Cells Subsets in Humans with Tolerance and Chimerism after Renaland Hematopoietic Cell Transplantation Dejbakhsh-Jones, S., Scandling, J., Busque, S., Nador, R., Hongo, D., Benike, C., Mukhopadhyay, A., Engleman, E., Strober, S. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2009: S30
  • Induced Tolerance to Liver Allografts Involves Apoptosis of Intragraft T Cells and the Generation of CD4+CD25+FoxP3+T Regulatory Cells. Fujiki, M., Esquivel, C. O., Martinez, O. M., Strober, S., Krams, S. M. WILEY-BLACKWELL PUBLISHING, INC. 2009: 662
  • Identification of Novel Radiation Induced Immune Signaling Changes in Antigen Presenting Cells 51st Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Parker, J. J., Jones, J. C., Strober, S., Knox, S. ELSEVIER SCIENCE INC. 2009: S545–S545
  • Differences in Bcl-2 Expression by T Cell Subsets Alter Their Balance After in vivo Irradiation to Favor Regulatory NKT Cells and CD4(+)CD25(+) T Cells in Wild Type But Not p53(-/-) Mice 9th Annual Meeting of the Federation-of-Clinical-Immunology-Societies Yao, Z., Jones, J., Liu, Y., Strober, S. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2009: S111–S111
  • Chimerism and Tolerance after Combined Human Kidney and Hematopoietic Cell Transplantation Using Conditioning with Total Lymphoid Irradiation and Anti-Thymocyte Globulin 50th Annual Meeting of the American-Society-of-Hematology/ASH/ASCO Joint Symposium Lowsky, R., Shizuru, J., Busque, S., Scandling, J., Sarwal, M., Jones, S., Benike, C., Hoppe, R., Engleman, E., Strober, S. AMER SOC HEMATOLOGY. 2008: 758–58
  • Outcomes Following Allogeneic Hematopoietic Cell Transplantation (HCT) Using Non-Myeloablative Conditioning with Total Lymphoid Irradiation (TLI) and Anti-Thymocyte Globulin (ATG) Confirm a Low Incidence of Graft Versus Host Disease (GVHD) with Retained Anti-Tumor Activity. 50th Annual Meeting of the American-Society-of-Hematology/ASH/ASCO Joint Symposium Kohrt, H., Turnbull, B., Laport, G., Miklos, D., Shizuru, J., Johnston, L., Arai, S., Weng, W. K., Benjamin, J., Blume, K., Negrin, R., Lavori, P., Strober, S., Lowsky, R. AMER SOC HEMATOLOGY. 2008: 1136–37
  • Prophylactic Rituximab after Reduced Intensity Conditioning Transplantation Results in Low Chronic Gvhd 50th Annual Meeting of the American-Society-of-Hematology/ASH/ASCO Joint Symposium Arai, S., Sahaf, B., Jones, C., Zhender, J., Lowsky, R., Strober, S., Shizuru, J., Negrin, R., Johnston, L., Laport, G., Schaenman, J., Brown, J., Weng, W., Letsinger, R., Wong, R., Lavori, P., Miklos, D. AMER SOC HEMATOLOGY. 2008: 178–78
  • Tolerance to rat liver allografts after total lymphoid irradiation is mediated by CD4+CD25+FOXP3+T cells Fujiki, M., Esquivel, C. O., Martinez, O. M., Strober, S., Krams, S. M. BLACKWELL PUBLISHING. 2008: 484
  • Mechanisms of Predominance of the Natural Killer T subset after In Vivo Irradiation and Impact on Bone Marrow Transplantation Yao, Z., Liu, Y., Jones, J., Strober, S. FEDERATION AMER SOC EXP BIOL. 2008
  • Tolerance to rat liver allograft after total lymphoid irradiation is mediated by CD4+CD25+regulatory T cells Fujiki, M., Esquivel, C. O., Martinez, O. M., Strober, S., Krams, S. M. FEDERATION AMER SOC EXP BIOL. 2008
  • Simultaneous protection against allograft rejection and graft-versus-host disease after total lymphoid irradiation: Role of natural killer T cells TRANSPLANTATION Liu, Y. P., Li, Z., Nador, R. G., Strober, S. 2008; 85 (4): 607-614

    Abstract

    The use of combined organ and bone marrow transplantation has been studied extensively in rodent models to induce immune tolerance to organ grafts. However, bone marrow transplants with mature donor T cells can induce graft-versus-host disease even in human leukocyte antigen-matched humans. We determined whether total lymphoid irradiation can simultaneously protect against graft-versus-host disease while facilitating tolerance.To more closely model clinical studies, we added mature donor T cells to bone marrow grafts combined with heart grafts, and compared murine graft and host survival after conditioning with nonmyeloablative total body or total lymphoid irradiation and depletive anti-T-cell antibodies.Conditioning with total lymphoid irradiation protected hosts against both graft-versus-host disease and organ graft rejection. Although nonmyeloblative total body irradiation prevented organ graft rejection, all hosts succumbed to lethal graft-versus host disease. Induction of tolerance with total lymphoid irradiation and anti-T-cell antibodies was dependent on the presence of regulatory host natural killer T cells, and expression of CD1d on donor marrow but not heart graft cells.Conditioning with total lymphoid irradiation and anti-T-cell antibodies prevented host-versus-donor and donor-versus-host alloimmune responses. Tolerance required host natural killer T-cell recognition of CD1d on donor marrow cells.

    View details for DOI 10.1097/TP.0b013e31816361ce

    View details for Web of Science ID 000253513700017

    View details for PubMedID 18347541

  • Tolerance and chimerism after renal and hematopoietic-cell transplantation. New England journal of medicine Scandling, J. D., Busque, S., Dejbakhsh-Jones, S., Benike, C., Millan, M. T., Shizuru, J. A., Hoppe, R. T., Lowsky, R., Engleman, E. G., Strober, S. 2008; 358 (4): 362-368

    Abstract

    We describe a recipient of combined kidney and hematopoietic-cell transplants from an HLA-matched donor. A post-transplantation conditioning regimen of total lymphoid irradiation and antithymocyte globulin allowed engraftment of the donor's hematopoietic cells. The patient had persistent mixed chimerism, and the function of the kidney allograft has been normal for more than 28 months since discontinuation of all immunosuppressive drugs. Adverse events requiring hospitalization were limited to a 2-day episode of fever with neutropenia. The patient has had neither rejection episodes nor clinical manifestations of graft-versus-host disease.

    View details for DOI 10.1056/NEJMoa074191

    View details for PubMedID 18216356

  • Brief report: Tolerance and chimerism after renal and hematopoietic-cell transplantation NEW ENGLAND JOURNAL OF MEDICINE Scandling, J. D., Busque, S., Dejbakhsh-Jones, S., Benike, C., Millan, M. T., Shizuru, J. A., Hoppe, R. T., Lowsky, R., Engleman, E. G., Strober, S. 2008; 358 (4): 362-368

    Abstract

    We describe a recipient of combined kidney and hematopoietic-cell transplants from an HLA-matched donor. A post-transplantation conditioning regimen of total lymphoid irradiation and antithymocyte globulin allowed engraftment of the donor's hematopoietic cells. The patient had persistent mixed chimerism, and the function of the kidney allograft has been normal for more than 28 months since discontinuation of all immunosuppressive drugs. Adverse events requiring hospitalization were limited to a 2-day episode of fever with neutropenia. The patient has had neither rejection episodes nor clinical manifestations of graft-versus-host disease.

    View details for Web of Science ID 000252507900006

  • Protective conditioning against GVHD and graft rejection after combined organ and hematopoietic cell transplantation Focused Workshop on Haploidentical Stem Cell Transplantation Strober, S. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2008: 48–54

    Abstract

    We have performed combined organ and hematopoietic cell transplantation using a similar conditioning regimen in mice and humans. In the mouse model of MHC-mismatched combined heart and marrow transplantation, we compared conditioning of BALB/c hosts with total lymphoid irradiation (TLI: 10 doses of 240 cGy each) targeted to the spleen, lymph nodes and thymus to conditioning with a single dose of sublethal total body irradiation (TBI; 450 cGy). Conditioning also included three injections of anti-thymocyte serum (ATS), in both groups. C57BL/6 heart grafts, marrow cells and blood mononuclear cells were transplanted 24 h after the completion of irradiation. Blood mononuclear cells were added to the marrow cells to engender severe graft versus host disease (GVHD) that is present after combined organ and hematopoietic cell transplantation in humans given non-myeloablative conditioning. Both TLI and TBI conditioned groups accepted the organ grafts and became stable chimeras. However, the TBI group all died of GVHD during the 100-day observation period. The TLI group survived during the same period without clinical signs of GVHD. These hosts were tolerized to the donor organ grafts, since third party grafts were rejected rapidly when transplanted after 100 days. When NK T-cell-deficient CD1d(-/-) BALB/c hosts were used instead of wild-type hosts in the TLI/ATS conditioned group, then all hosts survived but all rejected the organ grafts and almost all failed to develop stable chimerism. None developed GVHD. Since host NK T cells were required for graft acceptance and NK T cells are activated after recognition of CD1d on antigen presenting cells, we compared heart and marrow graft survival from wild-type versus CD1d(-/-) donors after transplantation to TLI and ATS conditioned wild-type hosts. Whereas marrow and heart grafts from wild-type donors were accepted, almost all grafts from CD1d donors were rejected. Grafts from control Jalpha18(-/-) donors that were NK T cell deficient but expressed CD1d were all accepted. The results indicate that host NK T cells facilitate graft acceptance by recognizing CD1d on donor cells. We applied the TLI conditioning regimen using 10 doses of 80 cGy each and 5 doses of rabbit ATG to human recipients of HLA-matched G-CSF "mobilized" blood mononuclear cell transplants for the treatment of leukemia and lymphoma [R. Lowsky, T. Takahashi, Y.P. Liu, et al., Protective conditioning for acute graft-versus-host disease. N. Engl. J. Med. 353 (2005) 1321-1331.]. Currently more than 100 transplants have been performed, and the incidence of acute GVHD has been about 4% when both MRD and MUD transplants are combined. Almost all recipients became complete chimeras after receiving grafts that contained 2-3x10(8) CD3(+) T cells/kg. In further studies, we applied the same TLI and ATG conditioning regimen to combined kidney and G-CSF "mobilized" blood stem cell transplantation from HLA-matched sibling donors. The hematopoietic grafts in the latter protocol were selected CD34(+) cells with 1x10(6) CD3(+) T cells/kg added back to the hematopoietic cells. Preliminary results indicate that stable mixed chimerism can be achieved using this protocol allowing for complete immunosuppressive drug withdrawal without GVHD or subsequent rejection episodes. Thus, conditioning with TLI based regimens can simultaneously protect against organ graft rejection and GVHD. Levels of chimerism are dependent upon the content of donor T cells in the hematopoietic graft.

    View details for DOI 10.1016/j.bcmd.2007.06.019

    View details for Web of Science ID 000252171800009

    View details for PubMedID 17827036

  • Mechanisms of predominance of the natural killer T subset after in vivo irradiation and impact on bone marrow transplantation Yao, Z., Liu, Y., Jones, J., Strober, S. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2008: S11
  • Immune cell subset survival after radiation Jones, J. C., Yao, Z., Strober, S., Knox, S. J. ELSEVIER SCIENCE INC. 2008: S167
  • Committed T cell progenitors in the bone marrow generate naive and memory phenotype T cells via intrathymic maturation and memory phenotype T cells only via extrathymic maturation Dajbakhsh-Jones, S., Strober, S. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2008: S56
  • Tolerance to combined organ and bone marrow transplantation after total lymphoid irradiation is dependent on both regulatory natural killer- and CD4+/CD25+T cells. 7th American Transplant Congress Nador, R. G., Liu, Y., Strober, S. WILEY-BLACKWELL. 2007: 482–482
  • Natural Killer (NK) T cells subset predominance after irradiation due to Bcl-2 protection against p53 dependent apoptosis Yao, Z., Liu, Y., Strober, S. AMER ASSOC IMMUNOLOGISTS. 2007
  • Rituximab infusion two months after total lymphoid irradiation-antithymocyte globulin (TLI-ATG) nonmyeloablative transplantation maintains B-cell disease control with minimal GVHD Tandem BMT Meeting 2007 Arai, S., Sahaf, B., Jones, C., Zehnder, J., Lowsky, R., Strober, S., Shizuru, J., Negrin, R., Johnston, L., Laport, G., Goldstein, K., Brown, J., Elder, L., Tierney, K., Lavori, P., Miklos, D. ELSEVIER SCIENCE INC. 2007: 103–
  • Interaction between host natural killer T cells and donor CD4(+)CD25(+) T-REG cells protects against GVHD after TLI/ATS host conditioning and allogeneic bone marrow transplaw tation Pillai, A. B., Dutt, S., George, T. I., Strober, S. A. ELSEVIER SCIENCE INC. 2007: 116
  • An immunoregulatory network of natural killer T cells and CD4+CD25+Foxp3+T cells protects against graft-versus-host disease Pillai, A., Dutt, S., George, T., Strober, S. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2007: S74
  • Allosensitized memory CD4 T cells induce chronic graft versus host disease. 48th Annual Meeting of the American-Society-of-Hematology Dutt, S., Tseng, D., George, T. I., Ermann, J., Liu, Y., Fathman, C. G., Strober, S. AMER SOC HEMATOLOGY. 2006: 137A–137A
  • Interaction between host natural killer T cells and donor CD4(+)CD25(+) T-reg cells protects against GVHD after TLI/ATS host conditioning and bone marrow transplantation. Pillar, A. B., Dutt, S., George, T. I., Strober, S. A. AMER SOC HEMATOLOGY. 2006: 136A
  • Clinical outcomes following allogeneic hematopoietic cell transplantation (HCT) using nonmyeloablative host conditioning with total lymphoid irradiation and anti-thymocyte globulin confirm a low incidence of graft versus host disease (GVHD) and retained graft anti-tumor activity. 48th Annual Meeting of the American-Society-of-Hematology Lowsky, R., Stockert-Goldstein, K., Laport, G., Miklos, D., Arai, S., Shizuru, J., Johnston, L., Blume, K., Negrin, R., Strober, S. AMER SOC HEMATOLOGY. 2006: 182A–182A
  • Rituximab infusion two months after nonmyeloablative transplantation maintains B-cell disease control with minimal GVHD. 48th Annual Meeting of the American-Society-of-Hematology Arai, S., Sahaf, B., Jones, C., Zehnder, J., Lowsky, R., Strober, S., Shizuru, J., Negrin, R., Johnston, L., Laport, G., Goldstein, K., Brown, J. (., Miklos, D. AMER SOC HEMATOLOGY. 2006: 823A–823A
  • Donor CD4(+) T and B cells in transplants induce chronic graft-versus-host disease with autoimmune manifestations BLOOD Zhang, C. Y., Todorov, I., Zhang, Z. F., Liu, Y. P., Kandeel, F., Forman, S., Strober, S., Zeng, D. F. 2006; 107 (7): 2993-3001

    Abstract

    Chronic graft-vs-host disease (GVHD) is a major cause of morbidity and mortality of long-term survivors of allogeneic hemato-poietic cell transplantation (HCT). Chronic GVHD can have features of an autoimmune collagen vascular disease with clinical manifestations similar to autoimmune scleroderma and systemic lupus erythematosus (SLE). However, the pathogenesis of chronic GVHD is poorly understood. It is unclear how autoreactive T and B cells are generated in chronic GVHD recipients. We have recently developed a new chronic GVHD model by transplantation of donor DBA/2 (H-2d) spleen cells into major histocompatibility complex (MHC)-matched but minor antigen-mismatched sublethally irradiated BALB/c (H-2d) recipients as well as athymic BALB/c(nu/nu) and adult-thymectomized BALB/c recipients. Both euthymic and athymic BALB/c recipients developed high levels of serum IgG autoantibodies, sclerodermatous skin damage, and glomerulonephritis. Disease induction required both donor CD25-CD4+ T and B cells in transplants. In contrast, donor CD25+CD4+ T regulatory (Treg) cells prevented the disease induction. These results indicate that host thymus is not required for induction of chronic GVHD and that quiescent autoreactive T and B cells in transplants from nonautoimmune donors may be activated and expanded to cause chronic GVHD with autoimmune manifestations in allogeneic recipients, and donor Treg cells can suppress this process.

    View details for DOI 10.1182/blood-2005-09-3623

    View details for Web of Science ID 000236656900066

    View details for PubMedID 16352808

  • Host invariant NKT cells preserve graft anti-tumor activity and mediate IL-4 dependent protection from GVHD. Pillai, A., Dutt, S., Strober, S. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2006: S9–S10
  • Protective conditioning for acute graft-versus-host disease - Reply NEW ENGLAND JOURNAL OF MEDICINE Lowsky, R., Negrin, R. S., Strober, S. 2005; 353 (25): 2718-2718
  • Memory CD4 T cells induce graft versus host disease. 47th Annual Meeting of the American-Society-of-Hematology Dutt, S., Tseng, D., Ermann, J., Liu, Y. P., George, T. I., Fathman, C. G., Strober, S. AMER SOC HEMATOLOGY. 2005: 380A–380A
  • Mechanisms by which NK T cells become the predominant T cell subset in mice after irradiation. Yao, Z. Y., Liu, Y. P., McIntire, J., Strober, S. AMER SOC HEMATOLOGY. 2005: 154B
  • Donor CD4(+) T and B cells in transplants induce autoimmune-like chronic graft versus host disease. 47th Annual Meeting of the American-Society-of-Hematology Zhang, C. Y., Todorov, I., Zhang, Z. F., Liu, Y. P., Kandeel, F., Forman, S., Strober, S., Zeng, D. F. AMER SOC HEMATOLOGY. 2005: 381A–381A
  • Stepwise development of committed progenitors in the bone marrow that generate functional T cells in the absence of the thymus 47th Annual Meeting of the American-Society-of-Hematology Dejbakhsh-Jones, S., Garcia-Ojeda, M. E., Chatterjea, D., Mukhopadhyay, A., Weissman, I. L., Strober, S. AMER SOC HEMATOLOGY. 2005: 923A–923A
  • Haploidentical non-myeloablative allogeneic hematopoietic cell transplantation (HCT) using total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) conditioning protects against acute graft versus host disease (GVHD) 47th Annual Meeting of the American-Society-of-Hematology Lowsky, R., Heydari, K., Sahaf, B., Shizuru, J., Laport, G., Johnston, L., Stockerl-Goldstein, K., Arai, S., Miklos, D., Blume, K., Herzenberg, L., Negrin, R., Strober, S. AMER SOC HEMATOLOGY. 2005: 814A–815A
  • Studies of tolerlance and chimerism after combined blood stem cell and kidney transplantation in humans Millan, M. T., Scandling, J. D., Shizuru, J., Lowsky, R., Strober, S. BLACKWELL PUBLISHING. 2005: 544
  • Interferon inducible proteins are novel autoantigens in systemic lupus erythematosus. Thibault, D. L., Hueber, W., Sylvester, T., Zeng, D., Strober, S., Utz, P. J. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2005: S122
  • Non-myeloablative conditioning of total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) protects against acute GVHD following allogeneic hematopoietic cell transplantation (HCT) but retains anti-tumor activity 46th Annual Meeting of the American-Society-of-Hematology Lowsky, R., Takahashi, T., Ping, Y., Shizuru, J., Negrin, R. S., Strober, S. AMER SOC HEMATOLOGY. 2004: 127A–127A
  • Analysis of CD161(+) T cells in human peripheral blood Takahashi, T., Dejbakhsh-Jones, S., Strober, S. AMER SOC HEMATOLOGY. 2004: 883A
  • Transcription factor Pbx1 is required for the development of double positive thymic T cells. Sanyal, M., Tung, J. W., Dejbakhsh-Jones, S., Strober, S., Herzenberg, L. A., Clear, M. L. AMER SOC HEMATOLOGY. 2004: 759A
  • Donor CD8+ T cells facilitate graft-versus-tumor effect via alloantigen rather than tumor-specific antigen recognition following murine myeloablative BMT. Pillai, A. B., Teo, P. A., Mukhopadhyay, A., Strober, S. AMER SOC HEMATOLOGY. 2004: 833A
  • Protection against graft-versus-host disease and retention of graft-versus-tumor effect after allogeneic BMT in mice conditioned with TLI and anti-thymocyte serum. Pillai, A., Teo, P., Strober, S. AMER SOC HEMATOLOGY. 2004: 833A
  • Tolerance induction using combined organ and hematopoietic cell transplantation following TLI/ATG conditioning. 4th International Workshop on Haploidentical Stem Cell Transplantation Lowsky, R., MILLAN, M., Scandling, J., Shizuru, J., Strober, S. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2004: 203–4
  • Identification of the source of IFN-g in murine lupus Siddique, A., Liu, Y. P., Strober, S. FEDERATION AMER SOC EXP BIOL. 2004: A1166
  • Granulocyte-colony stimulating factor (G-CSF) induces arthritis in LEW rats that correlates with the accumulation of myelomonocytic cells expressing CD8alpha. Slobodin, G., Iqbal, Satumtira, N., Dorris, M. L., Strober, S., Taurog, J. D. WILEY-LISS. 2003: 3646
  • Non-myeloablative conditioning with total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) for allogeneic hematopoietic cell transplantation (HCT) results in high levels of regulatory natural killer T cells and low incidences of acute GVHD and tumor relapse. 45th Annual Meeting and Exhibition of the American-Society-of-Hematology Lowsky, R., Jones, S. D., Mitra, S., Shizuru, J. A., Laport, G. G., Stockerl-Goldstein, K., JOHNSTON, L. J., Stuart, M. J., Herzenberg, L. A., Hoppe, R. T., Blume, K. G., Negrin, R. S., Strober, S. AMER SOC HEMATOLOGY. 2003: 152A–153A
  • Only the CD62L+ subpopulation of CD4+CD25+ regulatory T cells protects against lethal acute graft versus host disease. Dutt, S., Ermann, J., Hoffmann, P., Edinger, M., Negrin, R. S., Fathman, C. G., Strober, S. AMER SOC HEMATOLOGY. 2003: 950A
  • Different patterns of migration and expansion of blood and marrow CD4 T cells in lymphoid and non-lymphoid tissues result in a different capacity to induce graft-vs-host disease Zeng, D. F., Liu, Y. P., Dutt, S., Li, Z. Q., Higgins, J., Lewis, D. B., Strober, S. FEDERATION AMER SOC EXP BIOL. 2003: C59
  • CD4+CD25+ regulatory T cells act in secondary lymphoid organs to protect from lethal acute GVHD. Hoffmann, P., Edinger, M., Negrin, R. S., Fathman, C. G., Strober, S., Ermann, J. AMER SOC HEMATOLOGY. 2002: 143A
  • CD1d-reactive natural miler T cells mediate Th1-type immune response, augment autoantibody secretion and lupus development in NZB/NZW mice. Zeng, D. F., Liu, Y. P., Naidenko, O., Kronenberg, M., Strober, S. WILEY-LISS. 2002: S448
  • Transgenic T lymphocytes recognizing CD1 induce murine lupus and stimulate production of serum antibodies recognizing novel autoantigen complexes Hueber, W., Zeng, D., Strober, S., Utz, P. J. WILEY-LISS. 2002: S123
  • Rejection of cardiac Allografts by mixed chimeras can be prevented by regulatory CD1-reactive natural killer T cells. Higuchi, M., Zeng, E. F., Shizuru, J., Gworek, J., Dejbakhsh-Jones, S., Taniguchi, M., Strober, S. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2002: S4–S5
  • CD1d reactive natural killer T cells augment autoantibody secretion and lupus disease activity in NZB/NZW mice. Zeng, D. F., Liu, Y. P., Naidenko, O., Kronenberg, M., Strober, S. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2002: S70–S71
  • A non-myeloablative conditioning regimen followed by progenitor cell (CD34+) infusion after kidney transplantation can achieve mixed chimerism and immunosuppressive drug withdrawal Millan, M. T., Shizuru, J. A., Hoffmann, P., Dejbakhsh-Jones, S., Scandling, J. D., GRUMET, F. C., Tan, J. C., Salvatierra, O., Strober, S. FEDERATION AMER SOC EXP BIOL. 2002: A1030–A1030
  • CD25(+)CD4(+) regulatory donor T cells suppress acute graft-versus-host disease after allogeneic bone marrow transplantation. Hoffmann, P., Ermann, J., Fathman, C. G., Strober, S. AMER SOC HEMATOLOGY. 2001: 776A
  • Epidermal Langerhans cells in the adult derive from a stable self-reproducing population in the skin and not from a circulating precursor. Merad, M., Manz, M., Hoffmann, P., Strober, S., Weissman, I. L., Cyster, J. G., Engleman, E. G. AMER SOC HEMATOLOGY. 2001: 273A
  • Tolerance, mixed chimerism and protection against graft-versus-host disease after total lymphoid irradiation PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES Field, E. H., Strober, S. 2001; 356 (1409): 739-748

    Abstract

    Total lymphoid irradiation (TLI), originally developed as a non-myeloablative treatment for Hodgkin's disease, has been adapted for the induction of immune tolerance to organ allografts in rodents, dogs and non-human primates. Moreover, pretransplantation TLI has been used in prospective studies to demonstrate the feasibility of the induction of tolerance to cadaveric kidney allografts in humans. Two types of tolerance, chimeric and non-chimeric, develop after TLI treatment of hosts depending on whether donor bone marrow cells are transplanted along with the organ allograft. An advantageous feature of TLI for combined marrow and organ transplantation is the protection against graft-versus-host disease (GVHD) and facilitation of chimerism afforded by the predominance of CD4+ NK1.1(+) -like T cells in the irradiated host lymphoid tissues. Recently, a completely post-transplantation TLI regimen has been developed resulting in stable mixed chimerism and tolerance that is enhanced by a brief course of cyclosporine. The post-transplantation protocol is suitable for clinical cadaveric kidney transplantation. This review summarizes the evolution of TLI protocols for eventual application to human clinical transplantation and discusses the mechanisms involved in the induction of mixed chimerism and protection from GVHD.

    View details for Web of Science ID 000169357600014

    View details for PubMedID 11375076

    View details for PubMedCentralID PMC1088460

  • Resident CD8 T cells in bone marrow transplants mediate GVL activity without GVHD; Blood CD8 T cells mediate severe GVHD. Zeng, D. F., Lan, F. S., Huie, P., Higgins, J., Strober, S. AMER SOC HEMATOLOGY. 2000: 551A-+
  • Recombinant human granulocyte colony-stimulating factor (rhG-CSF) changes the cellular composition of the T cell compartment in murine bone marrow. Hoffmann, P., Strober, S. AMER SOC HEMATOLOGY. 2000: 765A
  • Granulocyte colony-stimulating factor-mobilized donor monocytes facilitate heart allograft acceptance 6th Congress of the Asian-Society-of-Transplantation Hayamizu, K., Yahata, H., Shinozaki, K., Tanji, H., Strober, S., Asahara, T. ELSEVIER SCIENCE INC. 2000: 2068–69

    View details for Web of Science ID 000166001400287

    View details for PubMedID 11120070

  • Reconstitution of T cells in vivo by committed T cell progenitors from the bone marrow Garcia-Ojeda, M. E., Dejbakhsh-Jones, S., Chatterjea-Matthes, D., Weissman, I. L., Strober, S. FEDERATION AMER SOC EXP BIOL. 2000: A921–A921
  • A host preparatory regimen prevents graft-versus-host disease (GVHD): Role of NK1.1(+) T cells Lan, F., Zeng, D., Strober, S. FEDERATION AMER SOC EXP BIOL. 2000: A1075
  • Induction of tolerance to EAE by injection of MBP68-86 pulsed peripheral monocytes Hirschberg, D. L., Brendolen, A., Strober, S., Steinman, L. FEDERATION AMER SOC EXP BIOL. 2000: A1102
  • A role for CD1 in the pathogenesis of lupus in NZB/NZW mice. Zeng, D., Lee, M., Tung, J., Brendolan, A., Strober, S. FEDERATION AMER SOC EXP BIOL. 2000: A965
  • Characterization of CD1hi B cells in autoimmune NZB/W mice Tung, J. W., Baumgarth, N., Lee, M. K., Herzenberg, L. A., Strober, S. FEDERATION AMER SOC EXP BIOL. 2000: A1210
  • Impaired development of the early T cell progenitor in the bone marrow of athymic nu/nu and Rag-2 (-)/(-) mice Chatterjea-Matthes, D., Garcia-Ojeda, M. E., Strober, S. FEDERATION AMER SOC EXP BIOL. 2000: A921
  • Which T cells are needed for engraftment and graft-versus-tumor effect? Strober, S. AMER SOC HEMATOLOGY. 1999: 79
  • Bone marrow NK1.1(+) and NK1.1(+) T cells reciprocally regulate lethal graft versus host diasease Zeng, D., Lewis, D., Jones, S., Lan, F., Garcia-Ojeda, M., Sibley, R., Strober, S. FEDERATION AMER SOC EXP BIOL. 1999: A613–A613
  • Arrest in the alternate T-cell maturation pathway in the bone marrow of genetically immunodeficient mice Chatterjea-Matthes, D., Garcia-Ojeda, M., Strober, S. FEDERATION AMER SOC EXP BIOL. 1999: A623–A623
  • An alternate pathway for T cell development supported by the bone marrow microenvironment: Recapitulation of thymic maturation. Garcia-Ojeda, M. E., Dejbaksh-Jones, S., Weissman, I. L., Strober, S. FEDERATION AMER SOC EXP BIOL. 1998: A302–A302
  • Mechanisms of murine lupus induction and prevention by transgenic T cells that recognize CD1 on B cells. Zeng, D., Dick, M., Jones, S., Strober, S. FEDERATION AMER SOC EXP BIOL. 1998: A606
  • Long term follow-up in patients treated with total lymphoid irradiation for lupus nephritis. Genovese, M. C., vanVollenhoven, R. F., Ramey, D., Fries, J., Strober, S. LIPPINCOTT-RAVEN PUBL. 1997: 169
  • Transgenic T cells that recognize CD1 on B cells induce or prevent murine lupus; Role of Th1 and Th2 subsets. Zeng, D., Dick, M., Amano, M., Cheng, L., Jones, S., Strober, S. MOSBY-YEAR BOOK INC. 1997: 1569
  • Expression of beta 2m associated and non-associated forms of CD1 on murine B cells. Amano, M., Strober, S. MOSBY-YEAR BOOK INC. 1997: 134
  • G-CSF reduces the capacity of blood mononuclear cells to induce GVHD: Impact on blood progenitor cell transplantation. Zeng, D., Jones, S., Strober, S. MOSBY-YEAR BOOK INC. 1997: 1900
  • Natural suppressor CD4(-)CD8(-)alpha beta(+) T cell lines express invariant TCRs that recognize CD1. Dick, M. D., Cheng, L., Ross, J., Strober, S. MOSBY-YEAR BOOK INC. 1997: 1211
  • A new model of murine lupus mediated by autoreactive transgenic T cells. Zeng, D., Cheng, L., Jones, S., Zimmer, T., Ross, J., Huie, P., Waggy, K., Sibley, R., Strober, S. FEDERATION AMER SOC EXP BIOL. 1996: 1758
  • TRANSPLANTATION OF ENRICHED AND PURGED PERIPHERAL-BLOOD PROGENITOR CELLS FROM A SINGLE APHERESIS PRODUCT IN PATIENTS WITH NON-HODGKINS-LYMPHOMA BLOOD Negrin, R. S., KUSNIERZGLAZ, C. R., Still, B. J., Schriber, J. R., Chao, N. J., Long, G. D., Hoyle, C., Hu, W. W., Horning, S. J., Brown, B. W., Blume, K. G., Strober, S. 1995; 85 (11): 3334-3341

    Abstract

    High-dose chemotherapy with or without radiotherapy followed by autologous transplantation of hematopoietic progenitor cells is an effective treatment for patients with high-risk or relapsed non-Hodgkin's lymphoma. Chemotherapy and/or hematopoietic growth factors have been used to mobilize progenitor cells in the peripheral blood for transplantation. However, the mobilized blood cell products have been found to be frequently contaminated with tumor cells, and techniques have not been developed to purge tumor cells from these products. In addition, the minimum number of hematopoietic progenitor cells required for engraftment has not yet been fully elucidated. We treated 21 patients with a single infusion of cyclophosphamide (4 g/m2) followed by daily administration of granulocyte colony-stimulating factor (G-CSF). After recovery of the white blood cell count, a single 3-hour apheresis collection was performed. The apheresis product was then applied to a discontinuous Percoll gradient. The low-density fractions resulting from this separation procedure were enriched for CD34+ progenitor cells (total cell yield, 19.5%; CD34+ cell recovery, 81.2%). These enriched cellular products were treated with a panel of anti-B cell or anti-T cell monoclonal antibodies and complement in an effort to remove residual tumor cells. After treatment of the patient with myeloablative therapies, the enriched and purged cells were reinfused. Hematologic recovery was rapid, with median neutrophil engraftment in 10 days [absolute neutrophil count (ANC), greater than 0.5 x 10(9)/L] and 11 days (ANC, greater than 1.0 x 10(9)/L). Median platelet transfusion independence required 13 days. The rapidity of multilineage engraftment correlated with the number of CD34+ cells per kilogram that were infused. Patients who received more than 2 x 10(6) CD34+ cells per kilogram had rapid hematologic engraftment, whereas those patients transplanted with less than 2 x 10(6) CD34+ cells per kilogram had slower platelet recovery. Modeling studies using a lymphoma cell line with a t(14; 18) chromosomal translocation demonstrated the successful removal of tumor cells assayed using the polymerase chain reaction (PCR) after the processing and purging. Four of the 21 patients had PCR-detectable lymphoma cells in the bone marrow and peripheral blood; however, the enriched and purged blood products reinfused in all four did not contain detectable tumor cells.(ABSTRACT TRUNCATED AT 400 WORDS)

    View details for Web of Science ID A1995RA13600043

    View details for PubMedID 7538824

  • TRANSPLANTATION OF MOBILIZED STEM-CELLS INTO ALLOGENEIC HOSTS WITHOUT SEVERE GRAFT-VERSUS-HOST DISEASE (GVHD) ZENG, D., JONES, S., STROBER, S. FEDERATION AMER SOC EXP BIOL. 1995: A784
  • TRANSPLANTATION OF ENRICHED AND PURGED PERIPHERAL-BLOOD PROGENITOR CELLS FROM A SINGLE APHERESIS PRODUCT IN PATIENTS WITH NON-HODGKINS-LYMPHOMA (NHL) NEGRIN, R. S., KUSNIERZGLAZ, C. R., STILL, B. J., SCHRIBER, CHAO, N. J., LONG, G. D., HOYLE, C., HU, W. W., HORNING, S. J., BROWN, B. W., BLUME, K. G., STROBER, S. W B SAUNDERS CO. 1994: A396
  • G-CSF INDUCED CO-MOBILIZATION OF HEMATOPOIETIC PROGENITOR CELLS (CD34+) AND NATURAL SUPPRESSOR CELLS (CD3+CD4-CD8-) IN NORMAL DONORS FOR ALLOGENIC PERIPHERAL-BLOOD CELL TRANSPLANTATION KUSNIERZGLAZ, C. R., STILL, B., ZUKOR, J., BLUME, K. G., STROBER, S., NEGRIN, R. S. W B SAUNDERS CO. 1994: A349
  • TRANSPLANTATION OF ENRICHED AND PURGED PERIPHERAL-BLOOD PROGENITOR CELLS (PBPCS) FROM A SINGLE APHERESIS PRODUCT IN PATIENTS WITH NON-HODGKINS-LYMPHOMA (NHL) NEGRIN, R. S., KUSNIERZGLAS, C. R., STILL, B., SCHRIEBER, CHAO, N. J., LONG, G. D., HORNING, S. J., BLUME, K. G., STROBER, S. S. CARDEN JENNINGS PUBL CO LTD. 1994: 777
  • TRANSPLANTATION OF DENSITY GRADIENT ENRICHED AND PURGED PERIPHERAL-BLOOD STEM-CELLS IN PATIENTS WITH LYMPHOMA - RAPID ENGRAFTMENT FROM SINGLE APHERESIS KUSNIERZGLAZ, C. R., STILL, B., BLUME, K. G., STROBER, S., NEGRIN, R. S. SLACK INC. 1994: A128
  • INVARIANT ANTIGEN RECEPTOR ALPHA-CHAIN AND BETA-CHAIN GENES IN CLONED CD4- CD8- ALPHA-BETA(+) T-CELLS CHENG, L., PALATHUMPAT, ZIMMER, T., LIANG, O., LIBLAW, R., STROBER, S. FEDERATION AMER SOC EXP BIOL. 1994: A242
  • PURGING OF PERIPHERAL-BLOOD MONONUCLEAR-CELLS ENRICHED FOR CD34+ CELLS BY PERCOLL GRADIENT CENTRIFUGATION FOLLOWED BY MONOCLONAL-ANTIBODY PLUS COMPLEMENT (MAB-C) TREATMENT NEGRIN, R. S., SCHRIBER, J., KUZNIERZGLAS, C., STILL, B., BLUME, K. G., STROBER, S. W B SAUNDERS CO. 1993: A295
  • ENRICHMENT OF CD34+ CELLS IN THE BONE-MARROW AND PERIPHERAL-BLOOD MONONUCLEAR-CELLS (PBMC) USING DENSITY GRADIENTS SCHRIBER, J., KUSNIERZGLAZ, C., NEGRIN, R. S., STILL, B., BLUME, K. G., STROBER, S. W B SAUNDERS CO. 1993: A653
  • A NOVEL IMMUNOSUPPRESSIVE CYTOKINE DERIVED FROM CD4-CD8-ALPHA(BETA)+ T-CELLS STROBER, S., NIKI, T., VANVLASSELAER, P. WILEY-LISS. 1993: 54
  • PRESERVATION OF OVARIAN-FUNCTION IN PATIENTS WITH LUPUS NEPHRITIS - CYCLOPHOSPHAMIDE VERSUS TOTAL LYMPHOID IRRADIATION HOCHFELD, M., DRUZIN, M., AUSTIN, S., STROBER, S., MCQUIRE, J. L. LIPPINCOTT-RAVEN PUBL. 1992: S208
  • THE GOAL OF SPECIFIC IMMUNOLOGICAL-UNRESPONSIVENESS IN CLINICAL KIDNEY-TRANSPLANTATION SEMINARS IN NEPHROLOGY Waer, M., Strober, S. 1992; 12 (4): 325-331

    View details for Web of Science ID A1992JC45900005

    View details for PubMedID 1410860

  • CHARACTERIZATION OF A NOVEL THYMOCYTE GROWTH COFACTOR MacNeil, I., Daley, C. M., CRABTREE, E., Fischer, M., Hannum, C., Campbell, D., Vandekerckhove, Y., VANVLASSELAER, P., Strober, S., Zlotnik, A. FEDERATION AMER SOC EXP BIOL. 1992: A1695–A1695
  • SURFACE-PLASMON IMMUNOASSAY APPLIED OPTICS Fontana, E., PANTELL, R. H., Strober, S. 1990; 29 (31): 4694-4704

    Abstract

    The most sensitive existing assays used to determine antibody levels in blood serum samples require a tracer material, e.g., radioisotope, fluorofore, or enzyme, to identify the specific analyte. Surface plasmon spectroscopy has been applied recently as a no-label technique for the assay of specific antibody solutions with the antigen proteins immobilized on a metal surface. It is found that the metal surface configuration originally proposed for the surface plasmon immunoassay (SPI) is unstable and unsuitable for the assay of specific antibodies in a large mixture of proteins such as in a blood serum. Nevertheless, by properly designing the metal surface structure, the SPI can be made an extremely practical device. Preliminary results for the assay of dinitrophenyl (DNP) and keyhole limpet hemocyanin (KLH) antibodies in blood serum samples, indicate that the SPI, in addition to providing a simple and fast measurement, is comparable with existing approaches, such as radioimmunoassy or enzyme-linked immunosorbent assay both in sensitivity and specificity.

    View details for Web of Science ID A1990EJ48300035

    View details for PubMedID 20577453

  • ACQUIRED IMMUNE TOLERANCE TO CADAVERIC RENAL-ALLOGRAFTS - A STUDY OF 3 PATIENTS TREATED WITH TOTAL LYMPHOID IRRADIATION NEW ENGLAND JOURNAL OF MEDICINE Strober, S., Dhillon, M., Schubert, M., Holm, B., Engleman, E., Benike, C., Hoppe, R., Sibley, R., Myburgh, J. A., Collins, G., Levin, B. 1989; 321 (1): 28-33
  • M-CELLS AND GRANULAR MONONUCLEAR-CELLS IN PEYER PATCH DOMES OF MICE DEPLETED OF THEIR LYMPHOCYTES BY TOTAL LYMPHOID IRRADIATION AMERICAN JOURNAL OF PATHOLOGY ERMAK, T. H., STEGER, H. J., STROBER, S., OWEN, R. L. 1989; 134 (3): 529–37

    Abstract

    The cytoarchitecture of Peyer's patches that were depleted of their lymphocytes by total lymphoid irradiation (TLI) was examined with particular attention to the effects on M cells in the follicle epithelium and on mononuclear cells in follicle domes underlying the epithelium. Five-month-old, specific pathogen-free Balb/c mice were irradiated with 200-250 rad/day, five times a week to a total dose of 3400-4250, and their Peyer's patches were either fixed for electron microscopy or frozen for immunohistochemistry 1-4 days after completion of irradiation. Control mice were examined at the same time intervals. Follicle domes of TLI mice had approximately one fourth the epithelial surface area of domes of control mice. Within the epithelium, lymphoid cells were virtually depleted after TLI, and yet the epithelium contained M cells. In control mice, most M cells were accompanied by lymphoid cells in invaginations of the apical-lateral cell membrane. In TLI mice, most M cells did not have such apical-lateral invaginations and were columnar shaped. Other than lacking lymphocytes, these cells appeared to be mature M cells. Some M cells did have lymphoid cells or granular mononuclear cells below their basal membranes, adjacent to the basal lamina. Below the epithelium, the proportion of granular mononuclear cells was greatly increased following TLI. The retention of M cells and the increase in proportion of granular mononuclear cells in follicle domes are consistent with selective depletion of lymphocytes following TLI. Persistence of M cells without lymphocytic invaginations after TLI suggests that M cells can differentiate in the absence of, or at least in the presence of very few, lymphocytes, and that invagination by lymphocytes is not necessary to maintain mature M cell morphology.

    View details for Web of Science ID A1989T492000005

    View details for PubMedID 2923183

    View details for PubMedCentralID PMC1879537

  • IMMUNOSUPPRESSIVE STRATEGIES FOR THE INDUCTION OF UNRESPONSIVENESS TO CANINE RENAL-ALLOGRAFTS TRANSPLANTATION PROCEEDINGS RAPAPORT, F. T., MEEK, A. G., HAYASHI, R., SONODA, K., STROBER, S. 1989; 21 (1): 381–84

    View details for Web of Science ID A1989U152300155

    View details for PubMedID 2650154

  • SYNERGISTIC EFFICACY OF STAGED TOTAL LYMPHOID IRRADIATION AND CYCLOSPORINE IN THE PREOPERATIVE PREPARATION OF HIGH-RISK HYPERIMMUNIZED CANINE RENAL-ALLOGRAFT RECIPIENTS TRANSPLANTATION PROCEEDINGS SONODA, K., MEEK, A. G., STROBER, S., HAYASHI, R., ISHIMARU, M., RAPAPORT, F. T. 1989; 21 (1): 1116–17

    View details for Web of Science ID A1989U152300460

    View details for PubMedID 2650070

  • OUTCOME OF GLOMERULAR INJURY IN LUPUS NEPHRITIS Chagnac, A., Sibley, R. K., Strober, S., Myers, B. D. NATURE PUBLISHING GROUP. 1989: 424–24
  • NEW THERAPIES FOR THE RHEUMATIC DISEASES BULLETIN ON THE RHEUMATIC DISEASES KLIPPEL, J. H., STROBER, S., WOFSY, D. 1989; 38 (4): 1–8

    Abstract

    The investigational therapies of the rheumatic diseases reviewed in this issue are at various stages of clinical development. Methotrexate and sulfasalazine represent examples of chemotherapies in which the short-term efficacy and toxicities, at least in rheumatoid arthritis, have been carefully documented by controlled trials. The limited information available on cyclosporin A, combination chemotherapy, and radiotherapy is encouraging and appears to warrant additional, more extensive studies. In particular, randomized trials to determine the effects of these interventions on relevant long-term outcomes such as functional disability, organ failure, and life expectancy are necessary. Careful attention to the adverse consequences associated with these interventions, a limiting factor in many currently available therapies, will be mandatory. Disease modification by biologic agents holds the promise of ushering in an entirely new, more selective approach to therapy. A number of these biologic agents are currently at the threshold of clinical evaluation. In all likelihood, the scientific knowledge of pathogenic mechanisms operative in the rheumatic diseases gained through the use of these agents will be of equal importance to the therapeutic benefits.

    View details for Web of Science ID A1989AJ00100001

    View details for PubMedID 2670022

  • A PROCEDURE FOR GROWING HUMAN SPLENOCYTE CULTURES FOR USE IN THE CELL-MEDIATED LYSIS (CML) ASSAY SCHUBERT, M. S., DHILLON, M. D., STROBER, S. MOSBY-YEAR BOOK INC. 1989: 201
  • DONOR SPECIFIC IMMUNE UNRESPONSIVENESS IN TLI RENAL-TRANSPLANTATION DHILLON, M. D., SCHUBERT, M., HOLM, B., STROBER, S. MOSBY-YEAR BOOK INC. 1989: 225
  • CELLULAR MECHANISMS IN IMMUNE TOLERANCE AND TREATMENT OF AUTOIMMUNE-DISEASE - STUDIES USING TOTAL LYMPHOID IRRADIATION (TLI) JOURNAL OF AUTOIMMUNITY Strober, S., Farinas, M. C. 1988; 1 (6): 693-702
  • DEPLETION AND REPOPULATION OF LYMPHOCYTES IN PEYERS PATCHES OF MICE AFTER TOTAL LYMPHOID IRRADIATION LABORATORY INVESTIGATION ERMAK, T. H., STEGER, H. J., OWEN, R. L., STROBER, S. 1988; 59 (5): 591–97

    Abstract

    The depletion and repopulation of lymphocytes in specific cellular domains of mouse Peyer's patches were examined following total lymphoid irradiation (TLI). BALB/c mice 5-months-old were given 17 fractionated doses of irradiation to a total of 3400 to 4250 rads over a 4-week period, and Peyer's patches were examined by immunohistochemistry at 1 to 4 days and 1 to 4 weeks after TLI. Cryostat sections were labeled with monoclonal antibodies directed against B220 (B cells), Thy-1.2 (all T cells), L3T4 (helper T cells), and Ly-2 (cytotoxic/suppressor T cells). In depleted mice, Peyer's patches were greatly reduced in size in comparison to controls, although the structural framework of follicles, domes, and interfollicular areas was still present. B cells in follicles were reduced to a small core of B220+ cells interspersed with nonlymphocytic cells. T cells were virtually eliminated from the patch except for a small population of Thy-1.2+ cells that were neither L3T4+ nor Ly-2+ in follicle domes. During early stages of repopulation at 1 to 2 weeks after TLI, follicles increased in size and were populated by helper T cells but Peyer's patches lacked discrete interfollicular T cell regions. At 3 to 4 weeks after TLI, T cell regions were found in interfollicular areas. The results indicate that morphologically distinct cellular domains are maintained in Peyer's patches after TLI which are sequentially repopulated by immigrating lymphocytes.

    View details for Web of Science ID A1988R030300004

    View details for PubMedID 2903270

  • SYNERGISTIC EFFECTS OF COMBINED IMMUNOSUPPRESSIVE MODULATION .1. UNRESPONSIVENESS TO DENDRITIC CELL DEPLETED RENAL-ALLOGRAFTS IN DOGS EXPOSED TO TOTAL-LYMPHOID IRRADIATION TRANSPLANTATION RAPAPORT, F. T., MEEK, A., MIURA, S., HAYASHI, R., ARNOLD, A. N., STROBER, S. 1988; 45 (4): 682–86

    Abstract

    Attenuation of the allogeneic stimulus provided by dendritic cells (DC) was achieved by irradiation of the donors, followed by their reconstitution with bone marrow from the prospective DLA-identical recipient. Following long-term (131-187 days) recovery free of graft-versus-host (GVH) disease, the chimeric kidneys were placed into the corresponding recipients; such allografts were rejected at 55, 55, and 60 days, respectively. Four other recipients were conditioned with 1750-1790 cgy of total lymphoid irradiation (TLI) and were then given a similar chimeric kidney from the corresponding partner. These allografts currently survive for 296, 295, 290, and 252 days, respectively. A third group of four dogs was exposed to TLI prior to transplantation of a normal DLA-identical kidney. These grafts were rejected at 20, 42, 46, and 242 days, respectively. Thirteen DLA-identical renal allografts transplanted into normal dogs survived for 13-38 days (mean survival time = 28.6 days). Depletion of allogeneic DC alone, or TLI alone, produced relative prolongations in allograft survival in canine recipients. Combined use of these two modalities, however, resulted in long-term allogeneic unresponsiveness in the recipients.

    View details for DOI 10.1097/00007890-198804000-00003

    View details for Web of Science ID A1988N111800003

    View details for PubMedID 3282348

  • PREOPERATIVE PREPARATION OF HIGH-RISK, SPECIFICALLY HYPERIMMUNIZED CANINE RENAL-ALLOGRAFT RECIPIENTS WITH TOTAL-LYMPHOID IRRADIATION AND CYCLOSPORINE TRANSPLANTATION RAPAPORT, F. T., MEEK, A. G., ARNOLD, A. N., MIURA, S., HAYASHI, R., STROBER, S. 1987; 44 (2): 185–95

    Abstract

    Hyperimmunized subjects are a particularly high-risk and rapidly growing group in the patient population awaiting renal transplantation. In a search for methods designed to ameliorate the prognosis in such cases, dogs of defined DLA genotype were sensitized with DLA incompatible skin allografts and injections of buffy coat. Each recipient was challenged with a renal allograft bearing the same DLA incompatibilities. Five dogs received kidney transplants, without any other treatment, and rejected their transplants at 2.5, 4, 5, 6, and 6.5 days, respectively. Another four dogs were given a 9-11-week course (1760 +/- 35 cGy) of total-lymphoid irradiation (TLI), followed by rabbit antithymocyte globulin (ATG); these animals rejected their renal allografts at 7, 8, 14, and 17 days, respectively. Five other dogs were treated with TLI and received cyclosporine (CsA) and methylprednisolone (MPd) daily until graft rejection. Their renal allografts survived for 7.5, 8.5, 20, 62, and 227 days, respectively. Renal allografts placed in normal recipients under the same conditions of donor-recipient DLA incompatibility had a mean survival time of 12.4 days (range: 10-18 days). At the time of transplantation, the specific anti-DLA antibody titers in the recipients were 81 to 243 in the untreated dogs; 27 to 81 in the TLI-ATG-treated group, and 3 to 243 in the TLI-CsA/MPd-treated group. The titers fell within 24-48 hr after renal transplantation, to 3 to 81 in the untreated sensitized dogs; they were 3 to 9 in the TLI-ATG-treated group, and were 9 to 243 in the TLI-CsA/MPd treated group. The cytotoxic antibody titers reached postoperative peaks of 6500 to 200,000 in the untreated dogs; 729 to 6500 in the TLI-ATG-treated dogs, and 243 to 6500 in the TLI-CsA/MPd-treated recipients. The combined use of TLI and CsA/MPd can significantly inhibit the capacity of immunized recipients to muster a secondary humoral response to the DLA antigen(s) used in the sensitization process; such treatment also abrogates the ability of the recipients to reject renal allografts bearing the same DLA specificities in accelerated fashion. This effect of TLI and cyclosporine may be of relevance to current severe problems in high-risk hyperimmunized human renal transplant candidates.

    View details for DOI 10.1097/00007890-198708000-00004

    View details for Web of Science ID A1987J743700004

    View details for PubMedID 3307042

  • RENAL-TRANSPLANT PATIENTS TREATED WITH TOTAL LYMPHOID IRRADIATION SHOW SPECIFIC UNRESPONSIVENESS TO DONOR ANTIGENS IN THE MIXED LEUKOCYTE REACTION (MLR) JOURNAL OF IMMUNOLOGY Chow, D., Saper, V., Strober, S. 1987; 138 (11): 3746-3750

    Abstract

    A group of 25 cadaveric renal transplant recipients received total lymphoid irradiation (TLI) before transplantation, rabbit anti-thymocyte globulin on alternate days for 10 days after transplantation, and low dose prednisone (5 to 10 mg/day) as the sole maintenance immunosuppressive therapy. Allograft function and the mixed leukocyte reaction (MLR) were monitored serially. After 18 to 30 mo, nine patients were selected on the basis of a return of the MLR such that the mean stimulation index to a panel of normal stimulator cells was greater than or equal to 5, a stable serum creatinine level which was less than or equal to 2 mg/dl, and a history of no more than one rejection episode. The MLR of these patients' post-transplant peripheral blood mononuclear leukocytes (PBML) against cryopreserved donor cells was compared with that against cryopreserved normal third-party cells. In control experiments, the MLR of cryopreserved pre-TLI recipient PBML or fresh normal PBML were tested against the same panel of donor and third-party stimulator cells. Seven of the nine recipients showed a pattern of specific unresponsiveness to the donor cells more than 18 mo after transplantation. Preliminary attempts to identify antigen specific suppressor cells were unsuccessful. The pattern of unresponsiveness may indicate a state of specific immune tolerance to the allogeneic graft.

    View details for Web of Science ID A1987H389200028

    View details for PubMedID 2953791

  • ENHANCEMENT OF HUMAN LYMPHOCYTE-T GROWTH BY HUMAN TRANSFERRIN IN THE PRESENCE OF FETAL BOVINE SERUM CELLULAR IMMUNOLOGY Gaston, J. S., Bacon, P. A., Strober, S. 1987; 106 (2): 366-375

    Abstract

    All dividing cells require transferrin as a growth factor. During in vitro culture of human lymphocytes, transferrin is usually supplied in the form of serum, either synergic or xenogenic (usually fetal bovine serum (FBS)). In the present work the growth of certain human T-cell lines was examined; these lines were derived from the synovium of rheumatoid arthritis patients and maintained in 10% FBS and 1% synovial fluid. Their growth especially at limiting dilutions was found to be strongly dependent on the presence of synovial fluid at low concentration (0.05-0.1%) in culture medium containing 10% FBS. Further studies indicated that this effect of synovial fluid was duplicated by human serum or plasma, and was due to the presence of human transferrin. A significant effect on T-cell growth was observed using 2 micrograms/ml human transferrin with optimal growth at 10-20 micrograms/ml. This requirement for human transferrin was not a peculiarity of the synovium-derived T-cell lines, but was observed with all T-cell lines tested irrespective of phenotype or function. These observations suggest that bovine transferrin is inadequate for T-cell growth, and that the growth enhancing properties of FBS do not primarily reflect the provision of transferrin. Since some T cells have recently been shown to be capable of secreting transferrin upon activation, endogenous synthesis of transferrin may be an important factor in the in vitro growth of T cells so that such cells would be selected when FBS is the source of serum used to grow human T-cell lines or clones.

    View details for Web of Science ID A1987H379200017

    View details for PubMedID 3105897

  • OUTCOME OF ACUTE GLOMERULAR INJURY IN PROLIFERATIVE LUPUS NEPHRITIS Kiberd, B. A., Strober, S., Myers, B. D. SLACK INC. 1987: A635–A635
  • COMPARATIVE TOXICITY OF TOTAL LYMPHOID IRRADIATION AND IMMUNOSUPPRESSIVE DRUG TREATED PATIENTS WITH INTRACTABLE RHEUMATOID-ARTHRITIS JOURNAL OF RHEUMATOLOGY Sherrer, Y., Bloch, D., Strober, S., Fries, J. 1987; 14 (1): 46-51

    Abstract

    Outcomes were compared between consecutive patients who had received either total lymphoid irradiation (TLI) or immunosuppressant treatment for intractable rheumatoid arthritis (RA). There were 33 TLI and 32 immunosuppressive recipients; all patients had failed standard therapy. Average followup from the start of therapy was 2.7 years for TLI and 5.9 years for immunosuppressive recipients. Final disability levels were the same in both groups; mortality was equal in both groups as well. There were more hospitalizations for infections in the TLI group and the infecting organisms tended to be staphylococcus or gram negative organisms. Apart from infections, there were more adverse effects reported in the immunosuppressive therapy group.

    View details for Web of Science ID A1987G460700013

    View details for PubMedID 3572934

  • ATTENUATION OF IMMUNOLOGICAL MEMORY IN CANINE RECIPIENTS HYPERIMMUNIZED WITH DLA-SPECIFIC ALLOANTIGENS TRANSPLANTATION PROCEEDINGS RAPAPORT, F. T., MEEK, A. G., ARNOLD, A., MIURA, S., STROBER, S. 1987; 19 (1): 464–68

    View details for Web of Science ID A1987G101300136

    View details for PubMedID 3547826

  • THE ROLE OF PASSENGER CELLS IN THE INDUCTION OF ALLOGENEIC UNRESPONSIVENESS TO CANINE RENAL-ALLOGRAFTS TRANSPLANTATION PROCEEDINGS MIURA, S., MEEK, A. G., ARNOLD, A. N., STROBER, S., RAPAPORT, F. T. 1987; 19 (1): 523–25

    View details for Web of Science ID A1987G101300158

    View details for PubMedID 3079162

  • LONG-TERM FOLLOW-UP OF RHEUMATOID-ARTHRITIS PATIENTS TREATED WITH TOTAL LYMPHOID IRRADIATION ARTHRITIS AND RHEUMATISM Tanay, A., Field, E. H., Hoppe, R. T., Strober, S. 1987; 30 (1): 1-10

    Abstract

    Total lymphoid irradiation was administered to 32 patients with intractable rheumatoid arthritis. Twenty-four patients showed at least a 25% improvement in 3 of 4 disease activity parameters, which persisted during the followup period of up to 48 months. Eight of the 32 patients required adjunctive immunosuppressive drug therapy to maintain improvement. Four patients died after total lymphoid irradiation; the causes of death were acute myocardial infarction (1 patient), pulmonary embolism (1 patient), and rheumatoid lung disease complicated by respiratory infection (2 patients). After therapy, patients exhibited a prolonged reduction in the number and function of circulating T helper cells.

    View details for Web of Science ID A1987F990900001

    View details for PubMedID 2949753

  • REGULATORY EFFECTS OF MAST-CELLS ON LYMPHOID-CELLS - THE ROLE OF HISTAMINE TYPE-1 RECEPTORS IN THE INTERACTION BETWEEN MAST-CELLS, HELPER T-CELLS AND NATURAL SUPPRESSOR CELLS CELLULAR IMMUNOLOGY Khan, M. M., Strober, S., Melmon, K. L. 1986; 103 (1): 41-53

    Abstract

    We have investigated the role of mast cells as modulators of lymphocyte function because the mast cells are concentrated in the areas of lymphoid storage; they are dependent upon T-cell growth factor for their proliferation; and they appear to be the principle if not sole storage site for histamine. We have tested the influence of mast cells on the proliferation of alloreactive cloned helper T cells, mixed leukocyte reactions, and the suppressive capacity of natural suppressor cells. We used an IL-3-dependent mast cell line that at high numbers (greater than 10(5)) suppressed and at low numbers (10(3) to 6 X 10(4)) augmented the proliferation of TH cells. Addition of histamine to cocultures enhanced the mast cell mediated proliferation of TH cells without directly affecting the helper cells. The action of histamine appeared to be mediated with H1 type receptors on these mast cells. Pretreatment of natural suppressor cells with supernatants from mast cell enhanced their suppressive capability. Here too, histamines enhanced suppression by the NS cell via histamine type 1 receptors on the natural suppressor cells. Our data suggest that mast cells may be a major modulator of the lymphoid cell immune function and demonstrate a role of histamine type 1 receptors in the interaction between mast cells, helper T cells, and natural suppressor cells.

    View details for Web of Science ID A1986E702800005

    View details for PubMedID 2879638

  • TREATMENT OF AUTOIMMUNE-DISEASE WITH TOTAL LYMPHOID IRRADIATION - CELLULAR AND HUMORAL MECHANISMS ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Strober, S., Kotzin, B., Field, E., Hoppe, R., Myers, B., Tanay, A. 1986; 475: 285-295

    View details for Web of Science ID A1986D835500027

    View details for PubMedID 3538972

  • THE EFFECTS OF DERIVATIVES OF HISTAMINE ON NATURAL SUPPRESSOR CELLS JOURNAL OF IMMUNOLOGY Khan, M. M., MARRLEISY, D., VERLANDER, M. S., Bristow, M. R., Strober, S., Goodman, M., Melmon, K. L. 1986; 137 (1): 308-314

    Abstract

    Histamine is an impressive modulator of immune functions at least via its effects on lymphoid cells. Its in vivo effects will not be used practically as long as they produce the profound cardiovascular and pulmonary effects for which the drug is known. A series of 13 congener derivatives and conjugates of histamine was constructed and was tested to investigate whether chemical alterations would result in pharmacologic actions on leukocytes that were more potent and effect specific than histamine. The new compounds, which contained spacer groups of varying lengths between ligand and carrier and with various aromatic modifying groups, showed potencies widely different from histamine when tested in natural suppressor cells. Some compounds showed selective effects on natural suppressor cells in that they were inactive on myocardial tissue, whereas other compounds were selectively active on the myocardium. Some compounds augmented the suppressive capacity of natural suppressor cells in mixed leukocyte reactions via H1 receptors. Our scheme might be more widely extrapolated to other low m.w. immune modulators in an attempt to make them lymphocyte specific. The data also encourage the in vivo testing of selected histamine analogues as selective modulators of immunity. Some of these modulators might be experimentally useful in vivo because they may lack actions in other tissues.

    View details for Web of Science ID A1986C898600048

    View details for PubMedID 3011908

  • APPROACHES TO HUMAN IMMUNE TOLERANCE IMMUNOLOGY TODAY STROBER, S. 1986; 7 (6): 153–55
  • TREATMENT OF NZB NZW MICE WITH TOTAL LYMPHOID IRRADIATION - LONG-LASTING SUPPRESSION OF DISEASE WITHOUT GENERALIZED IMMUNE SUPPRESSION JOURNAL OF IMMUNOLOGY Kotzin, B. L., Arndt, R., Okada, S., Ward, R., Thach, A. B., Strober, S. 1986; 136 (9): 3259-3265

    Abstract

    We used total lymphoid irradiation (TLI; total dose = 3400 rad) to treat the lupus-like renal disease of 6-mo-old female NZB/NZW mice. Similar to our past studies, this treatment resulted in a marked prolongation of survival, decrease in proteinuria, and decrease in serum anti-DNA antibodies compared with untreated littermate controls. Although there was no evidence of disease recurrence in TLI-treated mice until after 12 mo of age, the in vitro proliferative response to phytohemagglutinin by NZB/NZW spleen cells recovered within 6 wk such that responses were greater than control NZB/NZW animals. A similar recovery and overshoot after TLI were evident in the primary antibody response to the T cell-dependent antigen sheep red blood cells (SRBC). Both the total and IgG anti-SRBC antibody responses after TLI were greater than those of untreated NZB/NZW controls, and were comparable with those of untreated non-autoimmune mice. Despite this increased response to mitogens and antigens after TLI, we noted a decrease in spontaneous splenic IgG-secreting cells and a decrease in IgG but not IgM antinuclear antibody production. Nonspecific suppressor cells of the mixed leukocyte response were detectable in the spleens of NZB/NZW mice early after TLI. However, the disappearance of suppressor cells was not associated with recrudescence of disease activity. Furthermore, transfer of large numbers of spleen cells from TLI-treated NZB/NZW mice did not result in disease suppression in untreated age-matched recipients. In summary, treatment of NZB/NZW mice with TLI results in a prolonged remission in autoimmune disease, which is achieved in the absence of generalized immunosuppression.

    View details for Web of Science ID A1986C010600020

    View details for PubMedID 2937842

  • SURFACE IGG-BEARING CELLS RETAIN THE CAPACITY TO SECRETE IGM JOURNAL OF IMMUNOLOGY LaFrenz, D., Teale, J. M., Klinman, N. R., Strober, S. 1986; 136 (6): 2076-2079

    Abstract

    Our previous studies indicated that a large proportion of surface IgG+-primed B cells give rise to clones secreting IgM antibodies. Due to the implications of this result relative to molecular mechanisms of class switching, it was important to document that the surface IgG had been endogenously synthesized by the surface IgG+ cells and was not present as a result of cytophilic IgG. Therefore, spleen cells from immunized mice were treated sequentially with anti-immunoglobulin and protease which removed greater than 99% of surface immunoglobulin. After overnight incubation to allow resynthesis of surface immunoglobulin, the treated cells were sorted for surface IgG-bearing cells and were transferred to carrier-primed, irradiated adoptive recipients for analysis in the splenic focus assay. It was found that the majority of antibody-secreting clones derived from these surface IgG+ B cells still synthesized IgM. These data are discussed relative to current concepts of molecular mechanisms of immunoglobulin class switching.

    View details for Web of Science ID A1986A391000022

    View details for PubMedID 3485140

  • INDUCTION OF ALLOGENEIC UNRESPONSIVENESS TO PASSENGER CELL-FREE RENAL-ALLOGRAFTS BY TOTAL LYMPHOID IRRADIATION (TLI) MIURA, S., MEEK, A., ARNOLD, A., STROBER, S., RAPAPORT, F. T. FEDERATION AMER SOC EXP BIOL. 1986: 624
  • EFFECT OF TOTAL LYMPHOID IRRADIATION ON LEVELS OF SERUM AUTOANTIBODIES IN SYSTEMIC LUPUS-ERYTHEMATOSUS AND IN RHEUMATOID-ARTHRITIS ARTHRITIS AND RHEUMATISM Tanay, A., SCHIFFMAN, G., Strober, S. 1986; 29 (1): 26-31

    Abstract

    The effects of total lymphoid irradiation (TLI) on serum levels of autoantibodies, and of antibodies to diphtheria toxoid, tetanus toxoid, and pneumococcal polysaccharide in patients with lupus nephritis were compared with those previously observed in rheumatoid arthritis (RA) patients. Baseline levels of antibodies to diphtheria toxoid and tetanus toxoid decreased significantly after TLI in patients with lupus and RA, but antibody levels to pneumococcal polysaccharide remained unchanged. After TLI, the levels of antinuclear and anti-DNA antibodies were reduced significantly in lupus, but levels of rheumatoid factor, antinuclear, and antigranulocyte antibodies all tended to increase in RA.

    View details for Web of Science ID A1986C133500004

    View details for PubMedID 3947415

  • DISTRIBUTION OF B-CELLS, T-CELLS, AND NULL-CELLS IN PEYER PATCHES OF MICE AFTER TOTAL LYMPHOID IRRADIATION (TLI) ERMAK, T., OWEN, R. L., JONES, A. L., STROBER, S. SLACK INC. 1986: A46
  • TOTAL LYMPHOID IRRADIATION (TLI) FOR SEVERE RHEUMATOID-ARTHRITIS (RA) AND SYSTEMIC LUPUS (SLE) - EFFECT ON IGE ANTIBODY-RESPONSES TERR, A. I., MOSS, R. B., STROBER, S. MOSBY-YEAR BOOK INC. 1986: 136
  • EFFICACY AND SIDE-EFFECTS OF TOTAL LYMPHOID IRRADIATION (TLI) IN SEVERE RHEUMATOID-ARTHRITIS AND LUPUS NEPHRITIS - RISK OF MALIGNANCY AFTER THE USE OF TLI IN HODGKINS-DISEASE WITH AND WITHOUT CHEMOTHERAPY STROBER, S., HOPPE, R. T. PERGAMON-ELSEVIER SCIENCE LTD. 1986: 881
  • PRELIMINARY-OBSERVATIONS ON THE USE OF TOTAL LYMPHOID IRRADIATION, RABBIT ANTITHYMOCYTE GLOBULIN, AND LOW-DOSE PREDNISONE IN HUMAN CADAVER RENAL-TRANSPLANTATION TRANSPLANTATION PROCEEDINGS Sampson, D., LEVIN, B. S., Hoppe, R. T., BIEBER, C. P., Miller, E., Waer, M., KAPLAN, H. S., Collins, G., Strober, S. 1985; 17 (1): 1299-1303
  • EFFECTS OF CLONED MAST-CELLS ON LYMPHOID-CELLS KHAN, M. M., STROBER, S., MELMON, K. L. PERGAMON-ELSEVIER SCIENCE LTD. 1985: 341
  • T-CELL REGULATION OF THE THYMUS-INDEPENDENT ANTIBODY-RESPONSE TO "TRINITROPHENYLATED-BRUCELLA-ABORTUS (TNP-BA) JOURNAL OF IMMUNOLOGY Tanay, A., Strober, S. 1985; 134 (6): 3669-3674

    Abstract

    We have previously observed a reduction of the T cell-dependent primary antibody response to dinitrophenylated keyhole limpet hemocyanin, and an enhancement of the T cell-independent response to trinitrophenylated Brucella abortus (TNP-BA) in BALB/c mice after treatment with total lymphoid irradiation (TLI). To elucidate the relative contribution of T and B cells to the enhanced T cell-independent antibody responses after TLI, a syngeneic primary adoptive transfer system was utilized whereby irradiated hosts were reconstituted with unfractionated spleen cells or a combination of purified T and B cells from TLI-treated and untreated control mice. Antibody responses of purified splenic B cells from TLI-treated BALB/c mice (TLI/B) to TNP-BA were enhanced 10-fold as compared with those of unfractionated (UF) spleen cells or B cells from normal (NL) BALB/c mice (NL/UF and NL/B, respectively). Splenic T cells from normal animals (NL/T) suppressed the anti-TNP-BA response of TLI/B by more than 100-fold. NL/T neither suppressed nor enhanced the response of NL/B. On the other hand, T cells from TLI-treated mice (TLI/T) enhanced by 100-fold the anti-TNP-BA response of NL/B, but neither suppressed nor enhanced the response of TLI/B. Thus, T cells can regulate the "T cell-independent" antibody response to TNP-BA. However, experimental manipulation of the T and B cell populations is needed to demonstrate the regulatory functions.

    View details for Web of Science ID A1985AHR7300018

    View details for PubMedID 2859335

  • TREATMENT OF INTRACTABLE LUPUS NEPHRITIS WITH TOTAL LYMPHOID IRRADIATION ANNALS OF INTERNAL MEDICINE Strober, S., Field, E., Hoppe, R. T., Kotzin, B. L., Shemesh, O., Engleman, E., Ross, J. C., Myers, B. D. 1985; 102 (4): 450-458

    Abstract

    Ten patients with lupus nephritis and marked proteinuria (3.9 g or more/d) that did not respond adequately to treatment with prednisone alone or prednisone in combination with azathioprine were treated with total lymphoid irradiation in an uncontrolled feasibility study. Within 6 weeks after the start of total lymphoid irradiation, the serum albumin level rose in all patients in association with a reduction in the serum level of anti-DNA antibodies, an increase in the serum complement level, or both. Improvement in these variables persisted in eight patients followed for more than 1 year, with the stabilization or reduction of the serum creatinine level. Urinary leakage of albumin was substantially reduced in all patients. Side effects associated with radiotherapy included transient constitutional complaints in ten patients, transient blood element depressions in three, localized viral and bacterial infections in four, and ovarian failure in one. The results suggest that total lymphoid irradiation may provide an alternative to cytotoxic drugs in the treatment of lupus nephritis.

    View details for Web of Science ID A1985AEV5700002

    View details for PubMedID 3872090

  • EFFICACY OF TOTAL LYMPHOID IRRADIATION IN INTRACTABLE RHEUMATOID-ARTHRITIS - A DOUBLE-BLIND, RANDOMIZED TRIAL ANNALS OF INTERNAL MEDICINE Strober, S., Tanay, A., Field, E., Hoppe, R. T., Calin, A., Engleman, E. G., Kotzin, B., Brown, B. W., KAPLAN, H. S. 1985; 102 (4): 441-449

    Abstract

    Twenty-six patients participated in a randomized, double-blind study of the efficacy of total lymphoid irradiation in the treatment of intractable rheumatoid arthritis. All 26 patients, for whom therapy with gold compounds and penicillamine had failed, would ordinarily have been considered candidates for cytotoxic or antimetabolite drug therapy. Thirteen patients randomly assigned to receive full-dose total lymphoid irradiation (2000 rad) and 11 patients assigned to receive control low-dose total lymphoid irradiation (200 rad) completed radiotherapy. Alleviation of joint disease activity was significantly greater in the high-dose group as judged by morning stiffness, joint tenderness, and functional assessment (global composite score) at 3 and 6 months after radiotherapy. The high-dose group had a marked reduction in both T-lymphocyte function and numbers, but this finding was not observed in the low-dose group. Complications seen in the high-dose but not low-dose group included transient neutropenia, thrombocytopenia, pericarditis, and pleurisy.

    View details for Web of Science ID A1985AEV5700001

    View details for PubMedID 3883868

  • THE EFFECTS OF AUTACOIDS ON CLONED MURINE LYMPHOID-CELLS - MODULATION OF IL-2 SECRETION AND THE ACTIVITY OF NATURAL SUPPRESSOR CELLS JOURNAL OF IMMUNOLOGY Khan, M. M., Melmon, K. L., Fathman, C. G., HERTELWULFF, B., Strober, S. 1985; 134 (6): 4100-4106

    Abstract

    The pharmacologic effects of histamine and isoproterenol (autacoids) were studied on clones of murine T helper (TH) and natural suppressor (NS) cells. The data are consistent with receptors for the autacoids being nonrandomly distributed on phenotypically and functionally distinct clones. The effects of histamine on IL 2 secretion by TH cells could be either inhibitory or stimulatory, depending on the conditions of incubation with the autacoid. When TH cells were pretreated with histamine, their secretion of IL 2 was augmented; conversely, if histamine was added to the TH cells in the presence of antigen, IL 2 secretion was inhibited. The suppressor function of NS cells was enhanced by preincubation with histamine (10(-4) M) for 4 hr before the washed NS cells were added to responder and stimulator cells in mixed lymphocyte cultures. Two H1 receptor antagonists, mepyramine (10(-6) M) and pyrobutamine (10(-7) M), each competitively blocked the histamine activation of the NS cells, but an H2 receptor antagonist cimetidine (10(-5) M) did not alter the suppressor-enhancing function of histamine. Activation of NS cells did not occur if histamine was added with responder, stimulator, and co-cultured cells in MLR. The effects of each autacoid were additive in cytolytic T cells alone. The adenylate cyclase pools that can be stimulated by isoproterenol and histamine in cytolytic T cells may be independent of each other, but further work will be needed to prove this point.

    View details for Web of Science ID A1985AHR7300086

    View details for PubMedID 2859336

  • TREATMENT OF CADAVERIC RENAL-TRANSPLANT RECIPIENTS WITH TOTAL LYMPHOID IRRADIATION, ANTITHYMOCYTE GLOBULIN, AND LOW-DOSE PREDNISONE LANCET Levin, B., Collins, G., Waer, M., Girinsky, T., Hoppe, R. T., Miller, E., Bieber, C., Strober, S. 1985; 2 (8468): 1321-1325

    Abstract

    The ability of preoperative total lymphoid irradiation (TLI) to reduce the need for chronic immunosuppression after cadaveric renal transplantation was examined in 25 recipients who were given a brief course of antithymocyte globulin (ATG) postoperatively with daily low-dose prednisone (0.1-0.2 mg/kg) as the sole maintenance immunosuppressive drug. Patients were selected for the study on the basis of their low levels of cytotoxic antibodies. Grafts were not HLA-matched, and the mean interval between completion of TLI and transplantation was 9 days. During an observation period of up to 25 months, 2 grafts were lost because of rejection. There were two deaths due to disseminated viral infections and two to late cardiovascular complications. At the last observation point, the mean serum creatinine of the 19 patients with functioning grafts was 1.5 mg/dl, and the mean dose of prednisone was 10.2 mg/day. 10 of these patients did not have a rejection episode. Comparison of patients given TLI with a group given cyclosporin at the same institution showed similar graft survival but better graft function in the TLI group.

    View details for Web of Science ID A1985AVX7600002

    View details for PubMedID 2866386

  • CLONED NATURAL SUPPRESSOR-CELL LINES DERIVED FROM THE SPLEENS OF NEONATAL MICE JOURNAL OF EXPERIMENTAL MEDICINE SCHWADRON, R. B., GANDOUR, D. M., Strober, S. 1985; 162 (1): 297-310

    Abstract

    The establishment and characterization of cloned natural suppressor (NS) cell lines derived from the spleen of neonatal BALB/c mice are described. Cloned NS cells suppress the mixed leukocyte reaction (MLR) between normal adult responder and stimulator spleen cells with a 50-fold greater efficiency than fresh neonatal cells. Suppressive activity of both cells did not depend on the haplotype of the responder or stimulator cells, and was radioresistant. Cloned NS cells did not inhibit the uptake of [3H]thymidine by HT-2 cells proliferating in response to interleukin 2 (IL-2), nor the in vitro secretion of IL-1 by macrophages in response to lipopolysaccharide. Several experiments indicated that absorption of IL-2 could not explain the suppression of the MLR by the NS cells in the range of cell numbers tested. The results suggest that NS cells may suppress the MLR by interfering with early stages of T cell activation. The cell surface of a cloned NS cell line was examined using immunofluorescence staining, and was strongly positive for the Thy-1.2, Ly-5, and asialo-GM1 antigens. However, Lyt-1, Lyt-2, surface Ig, IE, MAC-1, and Fc and C3 receptor markers were not detected. In addition, NS cells showed no cytolytic activity against the YAC-1 target cell line. On the basis of these findings, cloned NS cells do not appear to be mature T cells, B cells, macrophages, or NK cells. The development of cloned NS cells may be useful in determining the identity and mechanism of action of nonspecific suppressor cells in the neonatal spleen, and their role in neonatal tolerance and maternal-fetal relationships.

    View details for Web of Science ID A1985ALW4900021

    View details for PubMedID 3159827

    View details for PubMedCentralID PMC2187699

  • INVITRO-PROPAGATION AND CLONING OF MURINE NATURAL SUPPRESSOR (NS) CELLS JOURNAL OF IMMUNOLOGY HERTELWULFF, B., Okada, S., Oseroff, A., Strober, S. 1984; 133 (5): 2791-2796

    Abstract

    During a short period of time after birth or after radiotherapy, the spleens of neonatal and adult TLI-treated mice contain suppressor cells of the mixed leukocyte reaction (MLR) and of graft-vs-host disease. The present report shows that the MLR suppressive activity of spleen cells from TLI-treated adult BALB/c mice can be maintained in long-term tissue culture by using conditioned medium. The suppressor cells can be cloned by limiting dilution, and reproducibly inhibit the [3H]TdR incorporation in the MLR at responder-to-suppressor cell ratios of 50:1. There is no antigen specificity or H-2 haplo-type restriction of the MLR suppression. The suppressor cells do not inhibit [3H]TdR per se, because no inhibition was observed in co-culture experiments with the EL4 tumor line or the IL 2-dependent HT-2 cell line. By using immunofluorescent staining techniques, the surface phenotype of the suppressor cells was found to be similar to that reported previously for cloned NK cells (Thy-1+, Lyt-1-, Lyt-2-, Ig-, Ia-, MAC-1-, asialo-GM1+). However, the suppressor lines showed no natural killer activity when YAC-1 target cells were used. Thus, the suppressor lines have been termed "natural suppressor" cells to indicate surface marker similarities to NK cells, both in vivo and in vitro, but different effector functions.

    View details for Web of Science ID A1984TP18300085

    View details for PubMedID 6237156

  • DOUBLE-BLIND CONTROLLED-STUDY OF TOTAL LYMPHOID IRRADIATION (TLI) IN RHEUMATOID-ARTHRITIS (RA) CALIN, A., CALIN, H. J., FIELD, E., TANAY, A., STROBER, S., HOPPE, R., KAPLAN, H. BRITISH MED JOURNAL PUBL GROUP. 1984: 121–22
  • TOTAL LYMPHOID IRRADIATION FOR THE TREATMENT OF MEMBRANOPROLIFERATIVE LUPUS GLOMERULONEPHRITIS FIELD, E., STROBER, S., SHEMESH, O., KOTZIN, B., HOPPE, R., FRIEDMAN, S., ENGLEMAN, E., KAPLAN, H., MYERS, B. SLACK INC. 1984: A463
  • NATURAL SUPPRESSOR (NS) CELLS, NEONATAL TOLERANCE, AND TOTAL LYMPHOID IRRADIATION - EXPLORING OBSCURE RELATIONSHIPS ANNUAL REVIEW OF IMMUNOLOGY STROBER, S. 1984; 2: 219–37
  • EFFECT OF TOTAL LYMPHOID IRRADIATION ON AUTOIMMUNE-DISEASE AND TRANSPLANTATION IMMUNITY - OVERVIEW JOURNAL OF IMMUNOLOGY STROBER, S. 1984; 132 (2): 968–70
  • INHIBITION OF THE INTERFERON-MEDIATED INDUCTION OF MACROPHAGE IA-ANTIGEN EXPRESSION BY A PROTEIN FACTOR PRODUCED BY SPLEEN-CELLS FROM TOTAL LYMPHOID IRRADIATED MICE STEIMER, K., GANDOUR, D., JONES, P., STROBER, S., PAULNOCKKING, D. GUSTAV FISCHER VERLAG. 1984: 121
  • DOUBLE-BLIND RANDOMIZED CONTROLLED TRIAL OF TOTAL LYMPHOID IRRADIATION (TLI) FOR THE TREATMENT OF INTRACTABLE RHEUMATOID-ARTHRITIS (RA) TANAY, A., STROBER, S., FIELD, E. H., CALIN, A., ENGLEMAN, E., HOPPE, R. T., KAPLAN, H. S. SLACK INC. 1984: A360
  • HISTAMINE ACTIVATES A MURINE NATURAL SUPPRESSOR-CELL KHAN, M. M., HERTELWULFF, B., STROBER, S., MELMON, K. L. MOSBY-YEAR BOOK INC. 1984: 250
  • STRATEGIES PROMOTING ALLOGRAFT ACCEPTANCE - AN OVERVIEW FEDERATION PROCEEDINGS STROBER, S. 1984; 43 (2): 261–62

    View details for Web of Science ID A1984SC68300023

    View details for PubMedID 6692947

  • THE ESTABLISHMENT AND CHARACTERIZATION OF LONG-TERM CULTURED NATURAL SUPPRESSOR (NS) CELL-LINES DERIVED FROM THE SPLEEN OF NEONATAL MICE SCHWADRON, R. B., STROBER, S. GUSTAV FISCHER VERLAG. 1984: 151–52
  • TOTAL LYMPHOID IRRADIATION CLINICS IN IMMUNOLOGY AND ALLERGY Kotzin, B. L., Strober, S. 1984; 4 (2): 331-358
  • USE OF TOTAL LYMPHOID IRRADIATION (TLI) IN STUDIES OF THE T-CELL-DEPENDENCE OF AUTOANTIBODY PRODUCTION IN RHEUMATOID-ARTHRITIS JOURNAL OF IMMUNOLOGY Tanay, A., Strober, S., Logue, G. L., SCHIFFMAN, G. 1984; 132 (2): 1036-1040

    Abstract

    The effect of total lymphoid irradiation (TLI) on T cell-dependent and -independent humoral immune responses was studied in patients with intractable rheumatoid arthritis (RA). The serum levels of several autoantibodies and of antibodies to diphtheria (DT) and tetanus (TT) toxoids and to pneumococcal polysaccharide (PPS; 12 antigenic types) were studied before and after TLI. In addition, the patients were given a booster injection of DT and TT and a single injection of pneumococcal vaccine after radiotherapy. Antibody levels to DT and TT decreased about twofold after TLI and did not rise significantly (p greater than 0.05) after a booster injection. However, there was no reduction in antibody levels to PPS after TLI, and a significant rise in titers was observed after a single vaccination (p less than 0.01). The serum levels of rheumatoid factor (RF), anti-nuclear antibody (ANA), and granulocyte associated IgG rose slightly after TLI. Thus, the autoantibodies and antibodies to polysaccharides appear to be relatively independent of helper T cell function, which is markedly reduced after TLI. On the other hand, antibodies to protein antigens such as DT and TT appear to be more closely dependent upon T helper function in man, as has been reported in rodents. The findings suggest that T cell-independent autoantibody responses alone do not maintain the joint disease activity in RA, because improvement in joint disease after TLI has been reported.

    View details for Web of Science ID A1984SA08700085

    View details for PubMedID 6361131

  • OPPOSITE EFFECTS OF TOTAL LYMPHOID IRRADIATION ON T-CELL-DEPENDENT AND T-CELL-INDEPENDENT ANTIBODY-RESPONSES JOURNAL OF IMMUNOLOGY Tanay, A., Strober, S. 1984; 132 (2): 979-984

    Abstract

    The effect of total lymphoid irradiation (TLI) on the primary antibody response to the dinitrophenylated heterologous protein, keyhole limpet hemocyanin (DNP-KLH), in complete Freund's adjuvant (CFA), and to the trinitrophenylated polysaccharide antigen, Brucella abortus (TNP-BA), was studied in BALB/c mice. The antibody response to both antigens was diminished in comparison with nonirradiated mice when antigens were injected within 3 days after TLI. When the mice were immunized 30 days after completion of TLI the antibody response to DNP-KLH in CFA was still diminished, but the antibody response to TNP-BA was enhanced 5- to 10-fold as compared with that of control animals. The opposite effect of TLI on the two antibody responses was also observed in a syngeneic primary adoptive transfer system.

    View details for Web of Science ID A1984SA08700075

    View details for PubMedID 6361136

  • ROLE OF NATURAL SUPPRESSOR CELLS IN ALLOGRAFT TOLERANCE FEDERATION PROCEEDINGS Strober, S., Okada, S., Oseroff, A. 1984; 43 (2): 263-265

    View details for Web of Science ID A1984SC68300024

    View details for PubMedID 6229422

  • NATURAL SUPPRESSOR (NS) CELLS FOUND IN THE SPLEEN OF NEONATAL MICE AND ADULT MICE GIVEN TOTAL LYMPHOID IRRADIATION (TLI) EXPRESS THE NULL SURFACE PHENOTYPE JOURNAL OF IMMUNOLOGY Oseroff, A., Okada, S., Strober, S. 1984; 132 (1): 101-110

    Abstract

    We studied the surface markers of suppressor cells of the mixed leukocyte reaction (MLR) that are transiently present in the spleens of neonatal mice after birth and of adult mice after total lymphoid irradiation (TLI). Approximately 80% of the mononuclear cells in the spleen, within the first few days after birth or after TLI, express neither the Thy-1 antigen nor surface immunoglobulin (Ig). After 30 days, less than 20% of mononuclear cells bear this null phenotype. With the use of the panning technique, we showed that the suppressors of the MLR are confined to the null cell population. The null suppressor cells are not macrophages because they did not carry macrophage markers identified by the monoclonal antibodies anti-MAC-1 and F4/80. In addition, the suppressor cells did not stain for nonspecific esterase and did not adhere firmly to plastic or glass. Spleen cells from TLI-treated mice maintained their suppressive capacity after culture in vitro for 6 to 8 wk. The cultured suppressor cells did not develop mature T cell, B cell, or macrophage markers during this time interval. Thus, the suppressor cells did not appear to be precursors of the latter cells. There was no clear relationship between the suppressor activity of the spleens and natural killer (NK) activity; the kinetics of these activities in newborn spleen appear to be inversely related. The suppressor cells, however, are similar to NK cells in that both are found in the absence of antigenic challenge, lack antigen specificity, and bear the null surface phenotype. Thus, we have termed the former cells natural suppressor (NS) cells.

    View details for Web of Science ID A1984RV65800019

    View details for PubMedID 6228575

  • REDUCED INVITRO IMMUNE-RESPONSES OF PURIFIED HUMAN LEU-3 (HELPER INDUCER PHENOTYPE) CELLS AFTER TOTAL LYMPHOID IRRADIATION JOURNAL OF IMMUNOLOGY Field, E. H., Engleman, E. G., TERRELL, C. P., Strober, S. 1984; 132 (2): 1031-1035

    Abstract

    Patients treated with total lymphoid irradiation (TLI) for intractable rheumatoid arthritis showed marked decreases in the in vitro proliferative responses of peripheral blood mononuclear cells (PBM) to antigens and mitogens. To determine whether an intrinsic deficit in helper/inducer cell proliferation contributed to decreased responses, cells of the helper/inducer phenotype were purified from the PBM of treated patients by using monoclonal anti-Leu-3 antibody and a modified panning procedure. The purified Leu-3 cells obtained after TLI showed a marked reduction in [3H]thymidine incorporation in response to allogeneic lymphocytes, PHA, Con A, and several protein antigens, as compared with that of cells from the same patients obtained before TLI. In addition, the quantity of Leu-3 surface antigen on the panned cells was reduced after TLI. The results suggest that TLI induces prolonged qualitative as well as quantitative changes in circulating Leu-3 T cells. These changes may contribute to the clinical effects of TLI.

    View details for Web of Science ID A1984SA08700084

    View details for PubMedID 6228587

  • SUPPRESSION OF POKEWEED MITOGEN-STIMULATED IMMUNOGLOBULIN PRODUCTION IN PATIENTS WITH RHEUMATOID-ARTHRITIS AFTER TREATMENT WITH TOTAL LYMPHOID IRRADIATION JOURNAL OF IMMUNOLOGY Kotzin, B. L., Strober, S., Kansas, G. S., TERRELL, C. P., Engleman, E. G. 1984; 132 (2): 1049-1055

    Abstract

    Patients with intractable rheumatoid arthritis (RA) were treated with total lymphoid irradiation (TLI, 2000 rad). We previously reported long-lasting clinical improvement in this group associated with a persistent decrease in circulating Leu-3 (helper subset) T cells and marked impairment of in vitro lymphocyte function. In the present experiments, we studied the mechanisms underlying the decrease in pokeweed mitogen stimulated immunoglobulin (Ig) secretion observed after TLI. Peripheral blood mononuclear cells (PBL) from TLI-treated patients produced 10-fold less Ig (both IgM and IgG) in response to pokeweed mitogen than before radiotherapy. This decrease in Ig production was associated with the presence of suppressor cells in co-culture studies. By using responder cells obtained from normal individuals (allogeneic system), PBL from eight of 12 patients after TLI suppressed Ig synthesis by more than 50%. In contrast, PBL from the same patients before TLI failed to suppress Ig synthesis. Suppression by post-TLI PBL was also demonstrated in an autologous system by using responder cells cryopreserved before TLI. Again, only cells obtained after TLI were suppressive in four of seven patients. PBL with suppressive activity contained suppressor T cells, and the latter cells bore the Leu-2 surface antigen. In 50% of the patients studied, suppressor cells were also found in the non-T fraction and were adherent to plastic. Interestingly, the Leu-2+ cells from TLI-treated patients were no more potent on a cell per cell basis than purified Leu-2+ cells obtained before TLI. Additional experiments suggested that the suppression mediated by T cells after TLI is related to the increased ratio of Leu-2 to Leu-3 cells observed after radiotherapy.

    View details for Web of Science ID A1984SA08700087

    View details for PubMedID 6228589

  • GLOMERULAR CAPILLARY WALL FUNCTION IN HUMAN LUPUS NEPHRITIS AMERICAN JOURNAL OF PHYSIOLOGY Friedman, S., Strober, S., Field, E. H., Silverman, E., Myers, B. D. 1984; 246 (5): F580-F591

    Abstract

    Eighteen patients with nephrotic-range proteinuria due to lupus nephritis were evaluated with a differential solute clearance technique. Renal plasma flow was similar to that in 17 healthy volunteer controls (506 +/- 75 vs. 503 +/- 32 ml/min, P = NS), while oncotic pressure in pre- and postglomerular plasma was depressed by 9.2 and 17.3 mmHg, respectively. These findings are consistent with elevation of net ultrafiltration pressure and suggest that glomerular hypofiltration (51 +/- 9 vs. 103 +/- 8 ml/min, P less than 0.001) was due to a lowered glomerular ultrafiltration coefficient (Kf). In lupus nephritis the fractional clearance of smaller dextrans (radii less than 50 A) was depressed, while that of larger dextrans (radii greater than 50 A) was elevated. A pore model of solute transport, when applied to the dextran filtration data, revealed a subpopulation of large protein-permeable pores in lupus nephritis not present in controls. Moreover, the fraction of glomerular filtrate permeating these enlarged pores correlated directly with the respective fractional clearances of albumin (r = 0.71) and immunoglobulin G (r = 0.75) in individual patients. Immunosuppression in nine patients was associated with an increase of the filtration rate and filtration fraction. Conversely, fractional protein clearances and the area fraction of the glomerular membrane occupied by large pores decreased. We conclude that human immune glomerular inflammation is manifested by a reduction of Kf and increased glomerular porosity and that these membrane alterations are partially reversible.

    View details for Web of Science ID A1984ST75100050

    View details for PubMedID 6720964

  • INDUCTION OF SPECIFIC UNRESPONSIVENESS TO HEART ALLOGRAFTS IN MONGREL DOGS TREATED WITH TOTAL LYMPHOID IRRADIATION AND ANTI-THYMOCYTE GLOBULIN JOURNAL OF IMMUNOLOGY Strober, S., Modry, D. L., Hoppe, R. T., Pennock, J. L., BIEBER, C. P., HOLM, B. I., Jamieson, S. W., Stinson, E. B., Schroder, J., Suomalainen, H., KAPLAN, H. S. 1984; 132 (2): 1013-1018

    Abstract

    The survival of heterotopic heart allografts was determined in mongrel dogs treated with total lymphoid irradiation (TLI) alone or in combination with other immunosuppressive agents. TLI alone (total dose, 1800 rad) minimally prolonged graft survival as compared with untreated controls. However, marked synergy was observed when TLI was combined with a 10-day post-transplant course of rabbit anti-dog thymocyte globulin (ATG). Approximately 40% of recipients given TLI and ATG showed specific unresponsiveness, as judged by the lack of rejection on serial biopsies for more than 1 yr and the prompt rejection of third party hearts. The addition of post-transplant azathioprine (90 to 180 days) to the TLI and ATG regimen increased the mortality of recipients and reduced the fraction of dogs showing specific unresponsiveness. Infusion of donor bone marrow cells at the time of heart transplantation failed to induce specific unresponsiveness in recipients given TLI alone or TLI in combination with post-transplant methotrexate, cyclosporine A, or ATG. The results indicate that the combination of TLI and a brief course of ATG without marrow transplantation was the most effective regimen for the induction of specific unresponsiveness in mongrel dogs.

    View details for Web of Science ID A1984SA08700081

    View details for PubMedID 6361129

  • Treatment of intractable rheumatoid arthritis with total lymphoid irradiation (TLI): immunological and clinical changes. Radiotherapy and oncology Strober, S., Field, E. M., Kotzin, B. L., Hoppe, R. T., ENGLEMAN, E. C., TANAY, A. S., KAPLAN, H. S. 1983; 1 (1): 43-52

    Abstract

    Eleven patients with intractable rheumatoid arthritis were treated with total lymphoid irradiation in a feasibility study. The mantle and the inverted Y fields were treated successively to a cumulative dose of 2000 rads. Nine of eleven patients showed at least a 35% improvement in three of four clinical parameters by six months and continued to maintain at least this level of improvement at their last observation points (13-28 months after TLI). There was a marked decrease in the percentage of total T cells and Leu-3 cells (helper), but an increase in the percentage of Leu-2 cells (suppressor/cytotoxic), resulting in a dramatic increase in the Leu-2/Leu-3 ratio. There was also a decrease in response to PHA, Con A and MLR.

    View details for PubMedID 6239305

  • MURINE GRANULOPOIESIS AFTER FRACTIONATED TOTAL LYMPHOID IRRADIATION AND ALLOGENEIC BONE-MARROW TRANSPLANTATION EXPERIMENTAL HEMATOLOGY Feiner, R. H., Strober, S., Greenberg, P. L. 1983; 11 (5): 410-417

    Abstract

    We investigated the effects of fractionated total lymphoid irradiation (TLI) and allogeneic bone marrow transplantation on murine granulopoiesis in order to evaluate the hemopoietic microenvironment of radiation chimeras (RC). BALB/c mice received 3400 rad TLI (17 daily 200 rad fractions) with or without 3 X 10(7) C57Bl/Ka marrow cells injected intravenously. Radiation resulted in prolonged depression of granulocyte-macrophage progenitor cells (CFU-GM) and endosteal colony-stimulating-activity (CSA) production in irradiated humeri. Allogeneic marrow transplantation partially restored endosteal CSA production and led to complete, although delayed, restoration of CFU-GM. Major compensatory granulopoiesis occurred in the spleen. Marrow fat-laden adherent cells (FLAC) were cultured in vitro from RC 30 weeks post TLI and transplantation. As determined by indirect immunofluorescence utilizing anti-H-2 antibodies, 23-25% of these cells reacted with antibodies possessing donor specificity. These findings suggest that the hemopoietic microenvironment, represented functionally by endosteal CSA production and morphologically by cultured FLAC, is transplantable by the intravenous route.

    View details for Web of Science ID A1983QP46000009

    View details for PubMedID 6343108

  • TREATMENT OF INTRACTABLE LUPUS NEPHRITIS WITH TOTAL LYMPHOID IRRADIATION FIELD, E., STROBER, S., KOTZIN, B., HOPPE, R., FRIEDMAN, S., ENGLEMAN, E., KAPLAN, H., MYERS, B. SLACK INC. 1983: A448
  • MECHANISMS OF TRANSPLANTATION TOLERANCE AFTER TLI STROBER, S., OKADA, S., OSEROFF, A. FEDERATION AMER SOC EXP BIOL. 1983: 1073
  • SURFACE PHENOTYPE OF SPLENIC SUPPRESSOR CELLS FOUND AFTER TOTAL LYMPHOID IRRADIATION (TLI) OSEROFF, A. R., OKADA, S., STROBER, S. FEDERATION AMER SOC EXP BIOL. 1983: 720
  • CHANGES IN T-CELL SUBSETS IN PATIENTS WITH RHEUMATOID-ARTHRITIS TREATED WITH TOTAL LYMPHOID IRRADIATION CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY Kotzin, B. L., Kansas, G. S., Engleman, E. G., Hoppe, R. T., KAPLAN, H. S., Strober, S. 1983; 27 (2): 250-260

    Abstract

    Patients with intractable rheumatoid arthritis (RA) were treated with total lymphoid irradiation (TLI, 2000 rads). We previously reported long-lasting clinical improvement associated with marked suppression of in vitro lymphocyte function in this group. In an attempt to better understand the mechanism of immunosuppression and clinical changes observed after TLI, we studied in greater detail changes in peripheral blood T-cell subsets identified by monoclonal antibodies. Before TLI, RA patients had a higher percentage of Leu-3 (helper subset) cells and a lower percentage of Leu-2 (suppressor/cytotoxic subset) cells than normals. Immediately after TLI, the absolute numbers of both Leu-2 and Leu-3 cells were reduced by at least 90%. Within 6-12 weeks, the number of Leu-2 cells returned to the pretreatment levels, but the levels of Leu-3 cells remained depressed for months thereafter. The lack of repopulation of Leu-3 cells resulted in a marked increase in the ratio of Leu-2 to Leu-3 cells as compared to pretreatment values (1.73 +/- 0.23 vs 0.39 +/- 0.06), and in a decrease in the percentage and absolute number of total T (Leu-1 and Leu-4) cells. The failure of Leu-3 cells (which mediate predominantly helper/inducer functions) to repopulate the peripheral blood may contribute to the prolonged clinical immunosuppression observed after TLI. Similar changes in T-cell subsets were not observed in RA patients given remittive drugs or low doses (200 rads) of radiotherapy. Thus, TLI differs from other treatment modalities with regard to its prolonged selective effect on the Leu-3 subset.

    View details for Web of Science ID A1983QM43600011

    View details for PubMedID 6409481

  • SUSTAINED IMPROVEMENT OF INTRACTABLE RHEUMATOID-ARTHRITIS AFTER TOTAL LYMPHOID IRRADIATION ARTHRITIS AND RHEUMATISM Field, E. H., Strober, S., Hoppe, R. T., Calin, A., Engleman, E. G., Kotzin, B. L., TANAY, A. S., CALIN, H. J., TERRELL, C. P., KAPLAN, H. S. 1983; 26 (8): 937-946

    Abstract

    Total lymphoid irradiation (TLI) was administered to 11 patients who had intractable rheumatoid arthritis that was unresponsive to conventional medical therapy, including aspirin, multiple nonsteroidal antiinflammatory drugs, gold salts, and D-penicillamine. Total lymphoid irradiation was given as an alternative to cytotoxic drugs such as azathioprine and cyclophosphamide. After radiotherapy, 9 of the 11 patients showed a marked improvement in clinical disease activity as measured by morning stiffness, joint tenderness, joint swelling, and overall functional abilities. The mean improvement of disease activity in all patients ranged from 40-70 percent and has persisted throughout a 13-28 month followup period. This improvement permitted the mean daily steroid dose to be reduced by 54%. Complications included severe fatigue and other constitutional symptoms during radiotherapy, development of Felty's syndrome in 1 patient, and an exacerbation of rheumatoid lung disease in another. After therapy, all patients exhibited a profound T lymphocytopenia, and a reversal in their T suppressor/cytotoxic cell to helper cell ratio. The proliferative responses of peripheral blood mononuclear cells to phytohemagglutinin, concanavalin A, and allogeneic leukocytes (mixed leukocyte reaction) were markedly reduced, as was in vitro immunoglobulin synthesis after stimulation with pokeweed mitogen. Alterations in T cell numbers and function persisted during the entire followup period, except that the mixed leukocyte reaction showed a tendency to return to normal values.

    View details for Web of Science ID A1983RC91100001

    View details for PubMedID 6882488

  • IDENTIFICATION OF DONOR-DERIVED ANTIGEN-SPECIFIC SUPPRESSOR CELLS IN MURINE BONE-MARROW CHIMERAS PREPARED WITH TOTAL-LYMPHOID IRRADIATION TRANSPLANTATION Okada, S., Palathumpat, V., Strober, S. 1983; 36 (4): 417-422

    Abstract

    The suppressor activity of the spleen cells from bone marrow chimeras prepared with total-lymphoid irradiation was analyzed in vitro. The chimeric spleen cells lacked responsiveness to host-type, but not to third-party, antigens in the mixed-leukocyte reaction (MLR) as judged by (3H)thymidine incorporation and the generation of cytolytic cells. When the donor-type chimeric spleen cells were used as cocultured cells in the MLR, modest nonspecific suppression of (3H)thymidine incorporation and potent antigen-specific suppression of the generation of the cytolytic cells was observed. The donor-type suppressor cells may play an important role in preventing graft-versus-host disease in vivo.

    View details for Web of Science ID A1983RL34000013

    View details for PubMedID 6226135

  • NATURE OF GLOMERULAR INJURY IN LUPUS NEPHRITIS Friedman, S., Field, E., Strober, S., Myers, B. D. SLACK INC. 1983: A98–A98
  • SPLEEN-CELLS FROM ADULT MICE GIVEN TOTAL LYMPHOID IRRADIATION OR FROM NEWBORN MICE HAVE SIMILAR REGULATORY EFFECTS IN THE MIXED LEUKOCYTE REACTION .1. GENERATION OF ANTIGEN-SPECIFIC SUPPRESSOR CELLS IN THE MIXED LEUKOCYTE REACTION AFTER THE ADDITION OF SPLEEN-CELLS FROM ADULT MICE GIVEN TOTAL LYMPHOID IRRADIATION JOURNAL OF EXPERIMENTAL MEDICINE Okada, S., Strober, S. 1982; 156 (2): 522-538

    Abstract

    We added spleen cells from adult BALB/c mice treated with total lymphoid irradiation (TLI) to the mixed leukocyte reaction (MLR) using a variety of responder and stimulator cells. The spleen cells nonspecifically suppressed the uptake of [3H]-thymidine and the generation of cytolytic cells regardless of the responder-stimulator combination used. We also examined the effect of the spleen cells on the generation of antigen-nonspecific and antigen-specific suppressor cells in the MLR. The experimental results suggest that the spleen cells from TLI-treated mice inhibit the generation of nonspecific suppressor cells, but do not inhibit the generation of antigen-specific suppressor cells. Thus, alloantigenic stimulation of normal responder cells in vitro in the presence of spleen cells from TLI-treated mice generates large numbers of antigen-specific suppressor cells, but few cytolytic cells or nonspecific suppressor cells. Similar nonspecific inhibition of the MLR was observed with neonatal spleen cells. This in vitro system provides a regulatory model for the induction and maintenance of tolerance in vivo, in which adult mice given TLI or neonatal mice accept allogeneic bone marrow transplants without graft-vs.-host disease.

    View details for Web of Science ID A1982PB10900016

    View details for PubMedID 6212626

    View details for PubMedCentralID PMC2186762

  • GENETIC-ASPECTS OF IGD-EXPRESSION .1. ANALYSIS OF THE C-MU-C-DELTA COMPLEX IN COMMITTED AND UNCOMMITTED DNA ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Blattner, F. R., Richards, J. E., Shen, A., Knapp, M., Strober, S., Gilliam, A. C., Jones, S., Cheng, H. L., Mushinski, J. F., Tucker, P. W. 1982; 399 (DEC): 1-14

    View details for Web of Science ID A1982PY68800001

    View details for PubMedID 6819799

  • TREATMENT OF INTRACTABLE RHEUMATOID-ARTHRITIS WITH TOTAL LYMPHOID IRRADIATION - 12-25 MONTH FOLLOW-UP FIELD, E., STROBER, S., KOTZIN, B., CALIN, A., ENGLEMAN, E. G., HOPPE, R. T., KAPLAN, H. S. SLACK INC. 1982: A512
  • LYMPHOID IRRADIATION FOR RHEUMATOID-ARTHRITIS - REPLY NEW ENGLAND JOURNAL OF MEDICINE HOPPE, R. T., KAPLAN, H. S., STROBER, S., KOTZIN, B. L. 1982; 306 (8): 487–88
  • SIMILAR CELLULAR MECHANISMS ARE ASSOCIATED WITH THE INDUCTION OF TRANSPLANTATION TOLERANCE IN ADULT MICE GIVEN TOTAL LYMPHOID IRRADIATION AND IN NEWBORN MICE OKADA, S., STROBER, S. FEDERATION AMER SOC EXP BIOL. 1982: 591
  • LYMPHOID IRRADIATION FOR RHEUMATOID-ARTHRITIS NEW ENGLAND JOURNAL OF MEDICINE STROBER, S., HOPPE, R. T., KAPLAN, H. S., KOTZIN, B. L. 1982; 307 (6): 375–76
  • SPLEEN-CELLS FROM ADULT MICE GIVEN TOTAL LYMPHOID IRRADIATION (TLI) OR FROM NEWBORN MICE HAVE SIMILAR REGULATORY EFFECTS IN THE MIXED LEUKOCYTE REACTION (MLR) .2. GENERATION OF ANTIGEN-SPECIFIC SUPPRESSOR CELLS IN THE MLR AFTER THE ADDITION OF SPLEEN-CELLS FROM NEWBORN MICE JOURNAL OF IMMUNOLOGY Okada, S., Strober, S. 1982; 129 (5): 1892-1897

    Abstract

    Spleen cells from newborn BALB/c mice were added to the mixed leukocyte reaction (MLR) between a variety of responder and stimulator cells. The newborn cells nonspecifically suppressed the uptake of (3H)-thymidine and the generation of cytolytic cells regardless of the responder-stimulator combination used. Suppressor cell activity fell rapidly during the first 4 days after birth, and could not be detected by day 20. Newborn spleen cells inhibited the generation of nonspecific suppressor cells during the MLR but did not inhibit the generation of antigen-specific suppressor cells. Thus, newborn spleen cells exhibit a pattern of regulation of the MLR similar to that reported previously for spleen cells from adult mice given total lymphoid irradiation (TLI). These regulatory interactions provide a model that explains the ease of induction of transplantation tolerance in vivo in newborn mice and in TLI-treated adult mice.

    View details for Web of Science ID A1982PM14700016

    View details for PubMedID 6181149

  • SIMULTANEOUS EXPRESSION OF IMMUNOGLOBULIN-MU AND DELTA-HEAVY CHAINS BY A CLONED B-CELL LYMPHOMA - A SINGLE COPY OF THE VH GENE IS SHARED BY 2 ADJACENT CH GENES PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES Knapp, M. R., Liu, C. P., Newell, N., Ward, R. B., Tucker, P. W., Strober, S., Blattner, F. 1982; 79 (9): 2996-3000

    Abstract

    The cloned murine B-cell lymphoma line (BCL1) that expresses surface IgM and IgD is considered to be a model for the immunoglobulin gene expression of the mature virgin B cell. Of particular interest is the mechanism by which a single VH gene is shared by two CH genes. We examined the organization of the immunoglobulin heavy chain genes in BCL1 DNA. A single arrangement of CH genes was found with the expressed VHDJH gene complex just 5' to the Cmu gene. The complete DNA sequence of the VH gene was determined. No rearrangement occurred in the intervening DNA between the JH and C mu genes or between the C mu and C delta genes. We conclude that dual expression of mu and delta heavy chains using a single VH gene is accomplished by alternate processing of a primary transcript that encompasses the the VHDJH complex and both CH genes.

    View details for Web of Science ID A1982NN41000054

    View details for PubMedID 6806821

    View details for PubMedCentralID PMC346335

  • ROLE OF IGD IN IMMUNOLOGICAL MEMORY ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LaFrenz, D., Teale, J. M., Strober, S. 1982; 399 (DEC): 375-388

    View details for Web of Science ID A1982PY68800033

    View details for PubMedID 6984620

  • LPS-INDUCED DIFFERENTIATION OF A MURINE B-CELL LEUKEMIA (BCL1) - CHANGES IN SURFACE AND SECRETED-IGM JOURNAL OF IMMUNOLOGY LaFrenz, D., KORETZ, S., Stratte, P. T., Ward, R. B., Strober, S. 1982; 129 (3): 1329-1335

    Abstract

    We examined the effect of LPS-induced differentiation on surface and secreted IgM in a cloned BCL1 in vitro cell line. Incubation of this cell line with LPS resulted in a decrease in the amount of membrane IgM, measured by both immunofluorescence and immunoprecipitation, and an increase in IgM secretion, measured by plaque-forming cells (PFC). Activation to high rate secretion was independent of cell cycle in synchronized cells and was independent of DNA synthesis because PFC formation was not inhibited by hydroxyurea. Almost all cells in the in vitro line were shown to contain large quantities of intracytoplasmic IgM before LPS activation. Thus, it would appear that the in vitro cell line represents a partially activated stage of differentiation compared to normal resting B cells or to the in vivo line of BCL1. Analysis of the two forms of mRNA coding for membrane and secreted IgM showed that, at least for cells at the level of differentiation examined here, the control of membrane IgM expression is post-transcriptional. The differentiation of resting B cells to the plasma cell level appears to consist of multiple stages of differentiation. The present data suggest that LPS provides at least two signals of activation. One induces the resting cell to synthesize cytoplasmic IgM, increase surface IgM, and to begin cell division. The second induces the secretion of intracytoplasmic IgM associated with a decrease in surface IgM.

    View details for Web of Science ID A1982PC12100079

    View details for PubMedID 6980922

  • SUPPRESSOR-CELL MECHANISMS IN TLI-TREATED MICE King, D. P., Strober, S. FEDERATION AMER SOC EXP BIOL. 1981: 1030–30
  • MANAGING THE IMMUNE-SYSTEM WITH TOTAL LYMPHOID IRRADIATION HOSPITAL PRACTICE STROBER, S. 1981; 16 (6): 77-&
  • THE TREATMENT OF INTRACTABLE RHEUMATOID-ARTHRITIS WITH TOTAL LYMPHOID IRRADIATION KOTZIN, B. L., STROBER, S., CALIN, A., ENGLEMAN, E., HOPPE, R., KAPLAN, H. S. SLACK INC. 1981: A558
  • THE USE OF TOTAL LYMPHOID IRRADIATION IN THE MANAGEMENT OF RHEUMATOID DISEASE (RA) CALIN, A., KOTZIN, B., STROBER, S., HOPPE, R., KAPLAN, H. BRITISH MED JOURNAL PUBL GROUP. 1981: 203–4
  • SUPPRESSOR CELLS OF THE MIXED LEUKOCYTE REACTION IN PATIENTS TREATED WITH TOTAL LYMPHOID IRRADIATION ENGLEMAN, E. G., KOTZIN, B., BENIKE, C., STROBER, S. SLACK INC. 1981: A527
  • REGULATION BY LYMPHOCYTE-T SUBSETS FEDERATION PROCEEDINGS STROBER, S. 1981; 40 (5): 1462

    View details for Web of Science ID A1981LK95600008

    View details for PubMedID 6971233

  • IMMUNOGLOBULIN CLASS COMMITMENT EXHIBITED BY LYMPHOCYTES-B SEPARATED ACCORDING TO SURFACE ISOTYPE JOURNAL OF IMMUNOLOGY Teale, J. M., LaFrenz, D., Klinman, N. R., Strober, S. 1981; 126 (5): 1952-1957

    Abstract

    In order to determine the extent to which B cells exhibit class commitment, the isotype(s) secreted by individual B cells and their progeny was studied in relation to the isotype(s) expressed on the surface of the B cell. Both primary and secondary B cells were separated according to cell surface isotypes and analyzed under optimal stimulation conditions using the T-dependent splenic focus assay. From these studies the following conclusions conclude be made: a) essentially all mature primary B cells appear to express mu on their surface; b) accordingly, the primary B cell population appears to be devoid of B cells expressing solely IgG on their surface; c) the majority of primary B cells in the presence of optimal T cell help have the potential for multiple class production; d) the secretion of IgA coincides with that of IgM and not IgG in its synthesis by immature B cells; e) a substantial proportion of memory B cells bear mu on their surface; f) memory B cells that lack s-mu are unable to yield clones secreting IgM; and g) a substantial proportion of memory B cells have the potential for multiple class production.

    View details for Web of Science ID A1981LL47100057

    View details for PubMedID 6971315

  • IMMUNOREGULATORY CHANGES INDUCED BY TOTAL LYMPHOID IRRADIATION .2. DEVELOPMENT OF THYMUS-LEUKEMIA ANTIGEN-POSITIVE AND ANTIGEN-NEGATIVE SUPPRESSOR T-CELLS THAT DIFFER IN THEIR REGULATORY FUNCTION JOURNAL OF EXPERIMENTAL MEDICINE King, D. P., Strober, S. 1981; 154 (1): 13-23

    Abstract

    BALB/c mice treated with total lymphoid irradiation (TLI) develop non-antigen-specific suppressor cells of the adoptive secondary antibody response and of the mixed leukocyte reaction. Suppressors of the adoptive anti-DNP response were eliminated by incubation of spleen cells with anti-Thy-1.2 or anti-thymus-leukemia (TL) antiserum and complement before cell transfer. Thymectomy before TLI prevented the appearance of the latter suppressor cells. On the other hand, suppressors of the MLR were eliminated by incubation of spleen cells with anti-Thy-1.2 but not anti-TL antiserum and complement. Thymectomy before TLI did not prevent their subsequent development. Thus, two subpopulations of suppressor T cells that differ in the expression of the TL surface antigen, dependence on the presence of the thymus, and in regulatory functions develop after TLI. The TL+, thymus-dependent cell suppresses the adoptive antibody response, and the TL-, thymus-independent cell suppresses the MLR.

    View details for Web of Science ID A1981LW55300002

    View details for PubMedID 6454753

    View details for PubMedCentralID PMC2186386

  • SUPPRESSION OF THE MIXED LEUKOCYTE RESPONSE AND OF GRAFT-VS-HOST DISEASE BY SPLEEN-CELLS FOLLOWING TOTAL LYMPHOID IRRADIATION (TLI) JOURNAL OF IMMUNOLOGY King, D. P., Strober, S., KAPLAN, H. S. 1981; 126 (3): 1140-1145

    Abstract

    Total lymphoid irradiation (TLI) was administered to mice as 17 fractions of 200 rads delivered to the major lymphoid organs. Spleen cells capable of suppressing the in vitro mixed leukocyte response (MLR) and in vivo graft-vs-host disease (GVHD) were found in mice after treatment with TLI. Suppression was not antigen specific and was markedly reduced by treatment of the spleen cells with anti-Thy-1.2 antiserum and complement. Suppressor activity declined with time after irradiation and disappeared within 30 to 40 days. The evidence suggests that the suppressor cells may prevent initial BM rejection and acute GVHD in allogeneic BM transplant recipients prepared with TLI.

    View details for Web of Science ID A1981LD29100061

    View details for PubMedID 6450802

  • THE RELATIONSHIP BETWEEN SURFACE-IMMUNOGLOBULIN ISOTYPE AND THE IMMUNE FUNCTION OF MURINE LYMPHOCYTES-B .5. HIGH-AFFINITY SECONDARY ANTIBODY-RESPONSES ARE TRANSFERRED BY BOTH IGD-POSITIVE AND IGD-NEGATIVE MEMORY B-CELLS JOURNAL OF IMMUNOLOGY LaFrenz, D., Strober, S., Vitetta, E. 1981; 127 (3): 867-872

    Abstract

    We examined the adoptive secondary anti-DNP responses restored by surface IgD+ and IgD- memory B cells. Several parameters that might affect the affinity and magnitude of the adoptive responses were studied: 1) time after priming of cell donors, 2) source of anti-IgD antibodies used for immunofluorescent cell staining, 3) adjuvant used for priming, 4) carrier protein used for priming, 5) amount of antigen used for the challenge of adoptive hosts, and 6) the strain of ice used as donors and recipients. In contrast to previous reports, the present results demonstrate that the selection of cells with high affinity antigen receptors can occur to the same extent in both the delta + and delta - memory cell pools. This suggests that the loss of surface IgD is not a necessary intermediate stage in the maturation of memory B cells.

    View details for Web of Science ID A1981MC71000011

    View details for PubMedID 6167629

  • INVITRO T-CELL MEDIATED FUNCTION IN PATIENTS WITH ACTIVE RHEUMATOID-ARTHRITIS ANNALS OF THE RHEUMATIC DISEASES Slavin, S., Strober, S. 1981; 40 (1): 60-63

    Abstract

    In-vitro synthesis of peripheral blood lymphocytes from patients with rheumatoid arthritis was measured after stimulation with phytohaemagglutinin (PHA) in a short-term, serum-free culture system. Diminished responses were found in 16 out of 17 consecutive patients with active disease. Normal PHA responsiveness was recovered by assaying Ficoll-Hypaque isolated E rosette forming cells in serum-free medium, indicating basically normal T cell function in RA. Preincubation of normal peripheral blood lymphocytes (or isolated E rosette forming cells) with sera obtained from patients with active RA for 30 minutes at 4 degrees C or 37 degrees C blocked PHA responsiveness in 34 out of 43 tests. This suggests that serum blocking factors may be responsible for reduced T cell reactivity in RA.

    View details for Web of Science ID A1981LA97600012

    View details for PubMedID 6970551

    View details for PubMedCentralID PMC1000657

  • IMMUNOREGULATORY CHANGES INDUCED BY TOTAL LYMPHOID IRRADIATION (TLI) .1. APPEARANCE OF A POPULATION OF CELLS BEARING THE THYMUS LEUKEMIA (TL) SURFACE-ANTIGEN IN THE LYMPH-NODES AND SPLEEN JOURNAL OF IMMUNOLOGY King, D. P., Strober, S., KAPLAN, H. S. 1981; 127 (3): 1085-1089

    Abstract

    BALB/c mice were treated with total lymphoid irradiation (TLI; 3400 rads) or single-dose, whole-body irradiation (WBI; 550 rads), and the lymph nodes and spleen were assayed for the level of H-2, Ia, Thy-1.2, Lyt-1.2, Lyt-2.2,3.2, and TL-bearing cells by an in vitro cytotoxicity assay. The level of cells bearing all these markers, except for TL, was similar to that observed in normal unirradiated mice. The level of TL+ cells was increased 10- to 20-fold in the TLI-treated mice as compared to WBI-treated mice or normals. The increased number of TL+ cells persisted for at lest 200 days after radiotherapy, and was not dependent upon irradiation of the thymus. However, thymectomy before TLI prevented the subsequent development of peripheral TL+ cells. The findings suggest that this abnormal subpopulation of T cells develops as a result of changes in the peripheral lymphoid tissue microenvironment induced by TLI.

    View details for Web of Science ID A1981MC71000055

    View details for PubMedID 6973579

  • TREATMENT OF INTRACTABLE RHEUMATOID-ARTHRITIS WITH TOTAL LYMPHOID IRRADIATION NEW ENGLAND JOURNAL OF MEDICINE Kotzin, B. L., Strober, S., Engleman, E. G., Calin, A., Hoppe, R. T., Kansas, G. S., TERRELL, C. P., KAPLAN, H. S. 1981; 305 (17): 969-976

    Abstract

    Eleven patients with intractable rheumatoid arthritis were treated with total lymphoid irradiation (total dose, 2000 rad) in an uncontrolled feasibility study, as an alternative to long-term therapy with cytotoxic drugs such as cyclophosphamide and azathioprine. During a follow-up period of five to 18 months after total lymphoid irradiation, there was a profound and sustained suppression of the absolute lymphocyte count and in vitro lymphocyte function, as well as an increase in the ratio of Leu-2 (suppressor/cytotoxic) to Leu-3 (helper) T cells in the blood. Persistent circulating suppressor cells of the mixed leukocyte response and of pokeweek mitogen-induced immunoglobulin secretion developed in most patients. In nine of the 11 patients, these changes in immune status were associated with relief of joint tenderness and swelling and with improvement in function scores. Maximum improvement occurred approximately six months after irradiation and continued for the remainder of the observation period. Few severe or chronic side effects were associated with the radiotherapy.

    View details for Web of Science ID A1981ML04900002

    View details for PubMedID 6456414

  • CARDIAC ALLOGRAFT SURVIVAL IN DOGS TREATED WITH TOTAL LYMPHOID IRRADIATION AND CHEMICAL IMMUNE SUPPRESSION SURGICAL FORUM Pennock, J. L., Strober, S., Reitz, B. A., Hoppe, R., KORETZ, S., BIEBER, C. P., KAPLAN, H. S., Stinson, E. B., Shumway, N. E. 1981; 32: 362-364
  • TOTAL LYMPHOID AND LOCAL JOINT IRRADIATION IN THE TREATMENT OF ADJUVANT ARTHRITIS ARTHRITIS AND RHEUMATISM Schurman, D. J., HIRSHMAN, H. P., Strober, S. 1981; 24 (1): 38-44

    View details for Web of Science ID A1981KY44000006

    View details for PubMedID 7470170

  • SURVIVAL OF PRIMATES FOLLOWING ORTHOTOPIC CARDIAC TRANSPLANTATION TREATED WITH TOTAL LYMPHOID IRRADIATION AND CHEMICAL IMMUNE SUPPRESSION TRANSPLANTATION Pennock, J. L., Reitz, B. A., BIEBER, C. P., Aziz, S., Oyer, P. E., Strober, S., Hoppe, R., KAPLAN, H. S., Stinson, E. B., Shumway, N. E. 1981; 32 (6): 467-473

    Abstract

    Fractionated total lymphoid irradiation (TLI) has been used for attempts at induction of a donor-specific tolerant-like state in allograft recipients and for immunosuppressive effects. Cyclosporin A (Cy A) has been shown to suppress rejection of organ grafts in many species including man. The present study was designed to test the effectiveness of TLI in combination with either CY A or rabbit anticynomolgus thymocyte globulin (ATG) and azathioprine. Thirty-one orthotopic cardiac allografts were performed using surface cooling and total circulatory arrest in outbred cynomolgus monkeys. TLI was administered preoperatively in fractions of 100 rad until a total of 600 or 1800 rad was achieved. Cy A was administered 17 mg/kg/day. All treatment groups demonstrated extended survival. Myocardial biopsies as early as 4 weeks were consistent with mild rejection in all treatment groups. No significant synergistic effect upon survival could be demonstrated utilizing TLI plus Cy A when compared with using Cy A alone. TLI (1800 rad) plus ATG and azathioprine was associated with a high incidence of early death attributable to leukopenia and infection. Cy A alone or in combination with TLI was associated with the development of lymphoid malignancy.

    View details for Web of Science ID A1981MU64300003

    View details for PubMedID 7041345

  • THE TREATMENT OF INTRACTABLE RHEUMATOID-ARTHRITIS WITH LYMPHOID IRRADIATION INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Strober, S., Kotzin, B. L., Hoppe, R. T., Slavin, S., Gottlieb, M., Calin, A., Fuks, Z., KAPLAN, H. S. 1981; 7 (1): 1-7

    View details for Web of Science ID A1981KZ62300001

    View details for PubMedID 7263332

  • ORGAN-TRANSPLANTATION IN MONGREL DOGS USING TOTAL LYMPHOID IRRADIATION (TLI) TRANSPLANTATION PROCEEDINGS KORETZ, S. H., Gottlieb, M. S., Strober, S., Pennock, J., BIEBER, C. P., Hoppe, R. T., Reitz, B. A., KAPLAN, H. S. 1981; 13 (1): 443-445

    View details for Web of Science ID A1981LF81600100

    View details for PubMedID 7022870

  • INDUCTION OF TRANSPLANTATION TOLERANCE AFTER TOTAL LYMPHOID IRRADIATION - CELLULAR MECHANISMS FEDERATION PROCEEDINGS Strober, S., King, D. P., Gottlieb, M., Hoppe, R. T., KAPLAN, H. S. 1981; 40 (5): 1463-1465

    View details for Web of Science ID A1981LK95600009

    View details for PubMedID 6452290

  • CELLULAR MECHANISMS OF TOLERANCE AFTER TOTAL LYMPHOID IRRADIATION (TLI) TRANSPLANTATION PROCEEDINGS Strober, S., King, D. P., Gottlieb, M. S., Hoppe, R. T., KAPLAN, H. S. 1981; 13 (1): 556-561

    View details for Web of Science ID A1981LF81600127

    View details for PubMedID 7022892

  • ORGAN-TRANSPLANTATION IN MONGREL DOGS USING TOTAL LYMPHOID IRRADIATION (TLI) Gottlieb, M. S., KORETZ, S. H., BIEBER, C. P., Hoppe, R. T., Reitz, B. A., KAPLAN, H. S., Strober, S. SLACK INC. 1980: A504–A504
  • THE TREATMENT OF RHEUMATOID-ARTHRITIS WITH TOTAL LYMPHOID IRRADIATION KOTZIN, B. L., STROBER, S., CALIN, A., HOPPE, R., KAPLAN, H. S. LIPPINCOTT-RAVEN PUBL. 1980: 707–8
  • Immunosuppression and organ transplantation tolerance using total lymphoid irradiation. Diabetes Slavin, S., Strober, S., Fuks, Z., Kaplan, H. S. 1980; 29 Suppl 1: 121–23

    Abstract

    Total lymphoid irradiation (TLI) is a method which delivers irradiation daily in fractionated doses (200 rads) to lymphoid organs while shielding bones, lungs, and the majority of the gastrointestinal tract. TLI is lymphocytopenic in mice, rats, dogs, and humans, and both T cells and B cells are eliminated from the circulation. During the recovery phase in mice, B cells appear before Thy 1.2-bearing T cells, and TL-positive T cells are abundant in the spleen and lymph nodes. These T cells exhibit nonspecific suppressive activity on antibody production and cell-mediated immune responses. TLI permits establishment of specific and long-lasting tolerance to alloantigens. Permanent acceptance of allogeneic bone marrow cells without graft-versus-host disease was achieved in rats and dogs across major histocompatibility barriers. Recipients were tolerant to allografts of skin, hearts, and kidney from animals syngeneic to marrow donors or to organs from the marrow donor. This approach may be suitable for pancreas transplantation in diabetes.

    View details for PubMedID 6986308

  • ROLE OF THE SPLEEN IN THE GROWTH OF A MURINE-B CELL LEUKEMIA SCIENCE Kotzin, B. L., Strober, S. 1980; 208 (4439): 59-61

    Abstract

    A spontaneous B cell leukemia (BCL1) grew progressively in normal BALB/c mice after injection of tumor cells but did not grow in splenectomized recipients. Despite the absence of progressive tumor growth, residual tumor cells with malignant potential were found in the peripheral blood of the splenectomized animals. Splenectomy performed after injection of tumor cells but before the development of marked leukocytosis also prevented progressive tumor growth and death of the host. Thus the spleen appears to be necessary for progressive proliferation of this lymphocytic leukemia early after passage in vivo.

    View details for Web of Science ID A1980JK81500020

    View details for PubMedID 6965803

  • INHIBITION OF T-CELL PROLIFERATION AND SLE-LIKE SYNDROME OF MRL-1 MICE BY WHOLE-BODY OR TOTAL LYMPHOID IRRADIATION JOURNAL OF IMMUNOLOGY Theofilopoulos, A. N., Balderas, R., Shawler, D. L., IZUI, S., Kotzin, B. L., Strober, S., Dixon, F. J. 1980; 125 (5): 2137-2142

    View details for Web of Science ID A1980KM42200041

    View details for PubMedID 6968773

  • SUPPRESSOR-CELL MECHANISMS IN TLI-TREATED MICE King, D. P., Strober, S. FEDERATION AMER SOC EXP BIOL. 1980: 1052–52
  • LONG-TERM EFFECTS OF SPLENECTOMY ON IMMUNOCOMPETENT CELLS OF ADULT MICE CELLULAR IMMUNOLOGY Slavin, S., ZANBAR, I., Strober, S. 1980; 55 (2): 444-455

    View details for Web of Science ID A1980KN58700018

    View details for PubMedID 7000378

  • AN INVITRO LINE OF THE B-CELL TUMOR BCL1 CAN BE ACTIVATED BY LPS TO SECRETE IGM JOURNAL OF IMMUNOLOGY GRONOWICZ, E. S., DOSS, C. A., Howard, F. D., Morrison, D. C., Strober, S. 1980; 125 (3): 976-980

    Abstract

    An in vitro line of the B cell tumor BCL1 was developed. The cell line carried u-, S-, and A-chains on the cell surface as judged by analysis of surface iodinated proteins but did not secret Ig. ASfter stimulation with LPS, limpid A, or bacterial lipoprotein, 20 to 40% of the tumor cells matured to IgM secretors when detected in a plaque assay. Two other polyclonal B cell activators, namely dextransulphate and PPD, had at most a marginal stimulatory effect. The ability of the cells to become activated to IgM secretion as well as the expression of cell surface IgM and IgD makes the BCL1 unique among murine B cell tumors.

    View details for Web of Science ID A1980KE22000003

    View details for PubMedID 6157730

  • CELLULAR BASIS OF GRAFT VERSUS HOST TOLERANCE IN CHIMERAS PREPARED WITH TOTAL LYMPHOID IRRADIATION JOURNAL OF EXPERIMENTAL MEDICINE Gottlieb, M., Strober, S., KAPLAN, H. S. 1980; 152 (3): 736-741

    Abstract

    BALB/c mice given allogeneic (C57BL/Ka) bone marrow cells after toal lymphoid irradiation become stable chimeras approximately 80% donor-type and 20% host-type cells in the spleen. The chimeras doe not develop graft vs. host disease (GVHD). Purified cells of C57BL/Ka origin from the chimeras mediated GVHD in lightly irradiated C3H (third party), but not in BALB/c (host-strain) mice. Thus graft vs. host tolerance in the chimeras could not be explained by complete immunodeficiency of donor-type cells, serum blocking factors, or suppressor cells of host (BALB/c) origin. Clonal deletion or suppression of lymphocytes reactive with host tissues remain possible explanations. The transfer of donor-type chimeric spleen cells to BALB/c recipients given 500-550 rad whole-body irradiation WBI led to stable mixed chimerism in approximately 50% of recipients. The cells were presumably acting as tolerogens because similarly irradiated BALB/c mice given (BALB/c X C57BL/Ka)F1 spleen or bone marrow cells also became stable mixed chimeras.

    View details for Web of Science ID A1980KG38900022

    View details for PubMedID 6447753

    View details for PubMedCentralID PMC2185928

  • IMMUNOSUPPRESSION AND TOLERANCE AFTER TOTAL LYMPHOID IRRADIATION (TLI) TRANSPLANTATION PROCEEDINGS Strober, S., Gottlieb, M., Slavin, S., King, D. P., Hoppe, R. T., Fuks, Z., BIEBER, C. P., KAPLAN, H. S. 1980; 12 (3): 477-482

    View details for Web of Science ID A1980KG77600023

    View details for PubMedID 6452725

  • ACCEPTANCE OF BONE-MARROW AND ORGAN ALLOGRAFTS AFTER TOTAL LYMPHOID IRRADIATION (TLI) Strober, S., Gottlieb, M. S., King, D. P., KORETZ, S. H., BIEBER, C. P., Reitz, B. A., Hoppe, R. T., KAPLAN, H. S. FEDERATION AMER SOC EXP BIOL. 1980: 1202–
  • ENGRAFTMENT OF ALLOGENEIC BONE-MARROW WITHOUT GRAFT VERSUS HOST-DISEASE IN MONGREL DOGS USING TOTAL LYMPHOID IRRADIATION TRANSPLANTATION Gottlieb, M., Strober, S., Hoppe, R. T., GRUMET, F. C., KAPLAN, H. S. 1980; 29 (6): 487-491

    View details for Web of Science ID A1980JX64100012

    View details for PubMedID 6996239

  • USE OF TOTAL LYMPHOID IRRADIATION (TLI) IN BONE-MARROW AND ORGAN-TRANSPLANTATION TRANSPLANTATION PROCEEDINGS Strober, S., Gottlieb, M., Slavin, S., Hoppe, R., GRUMET, F. C., KAPLAN, H. S. 1979; 11 (4): 1930-1933

    View details for Web of Science ID A1979JB52500065

    View details for PubMedID 43614

  • ALLOGENEIC MARROW TRANSPLANTATION AFTER TOTAL LYMPHOID IRRADIATION (TLI) - EFFECT OF DOSE-FRACTION, THYMIC IRRADIATION, DELAYED MARROW INFUSION, AND PRESENSITIZATION JOURNAL OF IMMUNOLOGY Gottlieb, M., Strober, S., KAPLAN, H. S. 1979; 123 (1): 379-383

    Abstract

    BALB/c mice infused with 30 x 10(6) C57BL/Ka bone marrow (BM) cells 1 day after treatment with fractionated total lymphoid irradiation (TLI) (17 fractions of 200 rads each) became stable mixed chimeras without clinical graft-vs-host disease (GVHD). Mice given 18 fractions of 100, 50, or 25 rads each followed 1 day later by C57BL/Ka BM did not become chimeric, indicating that a critical cumulative radiation dose is required for this effect. Animals given TLI with lead shielding placed over the thymus also developed stable chimerism without GVHD. Thus susceptibility to tolerance induction and protection from GVHD after TLI and allogeneic BM transplantation is not due to alteration of the thymic microenvironment by fractionated irradiation. A delay of 7 or 21 days between completion of TLI and BM administration resulted in a high incidence of graft rejection. Sensitization to minor histocompatibility antigens of the BM donor strain by blood transfusion either before or during TLI resulted in marrow graft rejection in a high percentage of animals.

    View details for Web of Science ID A1979HB56900060

    View details for PubMedID 376743

  • CHARACTERIZATION OF THE SPONTANEOUS MURINE B CELL LEUKEMIA (BCL1) .3. EVIDENCE FOR MONOCLONALITY BY USING AN ANTI-IDIOTYPE ANTIBODY JOURNAL OF IMMUNOLOGY Vitetta, E. S., Yuan, D., Krolick, K., Isakson, P., Knapp, M., Slavin, S., Strober, S. 1979; 122 (5): 1649-1654

    Abstract

    We have raised an anti-idiotypic antibody against the cell surface IgM of the murine BCL1 tumor cells. This antiserum reacts exclusively with the IgM expressed on the tumor cells and detects a unique population of cells in the spleen and blood of the tumor-bearing mice. When these cells are stimulated in vitro with LPS, they secrete an IgM bearing the same idiotype as the cell surface Ig. These results are discussed in terms of a model for the immunotherapy of a chronic lymphocytic leukemia-like syndrome in mice.

    View details for Web of Science ID A1979GU71100004

    View details for PubMedID 109513

  • TRANSPLANTATION TOLERANCE ACROSS MAJOR HISTOCOMPATIBILITY BARRIERS AFTER TOTAL LYMPHOID IRRADIATION TRANSPLANTATION Slavin, S., Fuks, Z., Strober, S., Kaplan, H., Howard, R. J., Sutherland, D. E. 1979; 28 (5): 359-361

    View details for Web of Science ID A1979HS41500001

    View details for PubMedID 392830

  • CHARACTERIZATION OF AN E-ROSETTE INHIBITOR (ERI) IN THE SERUM OF PATIENTS WITH HODGKIN DISEASE, AS A GLYCOLIPID BIEBER, M. M., KING, D. P., STROBER, S., KAPLAN, H. S. SLACK INC. 1979: A81
  • TREATMENT OF NZBXNZW DISEASE WITH TOTAL LYMPHOID IRRADIATION KOTZIN, B. L., STROBER, S. LIPPINCOTT-RAVEN PUBL. 1979: 631
  • SUPPRESSOR MECHANISMS IN SPECIFIC TRANSPLANTATION TOLERANCE ACROSS HISTOINCOMPATIBLE BARRIERS IN MICE SLAVIN, S., STROBER, S. WILEY-LISS. 1979: 318
  • STRUCTURAL DIFFERENCES BETWEEN U CHAINS FROM CELL-SURFACE AND SECRETED IGM YUAN, D., UHR, J. W., KNAPP, M., SLAVIN, S., STROBER, S., VITETTA, E. S. WILEY-LISS. 1979: 257
  • T-CELL MEDIATED IMMUNE RESPONSIVENESS IN RHEUMATOID-ARTHRITIS SLAVIN, S., STROBER, S. SLACK INC. 1979: A337
  • PROPAGATION OF IMMUNOLOGICAL MEMORY BY IGD-BEARING CELLS STROBER, S. FEDERATION AMER SOC EXP BIOL. 1979: 1465
  • GENERATION OF PROTEIN-SPECIFIC AND ALLOANTIGEN-SPECIFIC SUPPRESSOR CELLS FOLLOWING TOTAL LYMPHOID IRRADIATION IN MICE TRANSPLANTATION PROCEEDINGS Slavin, S., ZANBAR, I., Strober, S. 1979; 11 (1): 891-894

    View details for Web of Science ID A1979GQ02500194

    View details for PubMedID 156437

  • EFFECT OF TOTAL LYMPHOID IRRADIATION (TLI) ON THE PRIMARY AND SECONDARY ANTIBODY-RESPONSE TO SHEEP RED BLOOD-CELLS CELLULAR IMMUNOLOGY ZANBAR, I., Slavin, S., Strober, S. 1979; 45 (1): 167-174

    View details for Web of Science ID A1979GW53800016

    View details for PubMedID 455482

  • CHARACTERIZATION OF A SPONTANEOUS MURINE B-CELL LEUKEMIA (BCL1) .1. CELL-SURFACE EXPRESSION OF IGM, IGD, IA, AND FCR JOURNAL OF IMMUNOLOGY Knapp, M. R., Jones, P. P., Black, S. J., Vitetta, E. S., Slavin, S., Strober, S. 1979; 123 (3): 992-999

    Abstract

    The surface marker expression of a spontaneous B lymphocyte leukemia discovered in a BALB/c mouse (BCL1) was examined and found to include a subset of markers known to occur on normal B lymphocytes. The tumor cells bore surface Ig that included both mu- and delta-chains associated with the lambda light chain. Alloantigens coded for within the murine MHC, including H-2D, H-2K, and I-region products, were identified on the tumor cells. Although normal B lymphocytes are thought to express products coded for within both the I-A and I-E subregions, the BCL1 expressed only normal amounts of I-E subregion products. In addition, the H-2 and Ia antigens revealed by 2-dimensional gel electrophoresis exhibited an abnormal pattern of post-translational modifications. The Fc, but not the complement-receptor, was present on the surface of tumor cells. The presence of IgD, Ia antigens, and the responsiveness to lipopolysaccharide (see subsequent paper) have led us to postulate that the BCL1 tumor represents a later differentiative stage than murine B lymphocyte tumors previously described.

    View details for Web of Science ID A1979HH67000005

    View details for PubMedID 313960

  • RELATIONSHIP BETWEEN SURFACE-IMMUNOGLOBULIN ISOTYPE AND IMMUNE FUNCTION OF MURINE LYMPHOCYTES-B .4. ROLE OF IGD-BEARING CELLS IN THE PROPAGATION OF IMMUNOLOGICAL MEMORY JOURNAL OF IMMUNOLOGY ZANBAR, I., Strober, S., Vitetta, E. S. 1979; 123 (2): 925-930

    View details for Web of Science ID A1979HD95100067

    View details for PubMedID 313424

  • IMMUNOBIOLOGY OF A SPONTANEOUS MURINE B-CELL LEUKEMIA (BCL1) IMMUNOLOGICAL REVIEWS Strober, S., GRONOWICZ, E. S., Knapp, M. R., Slavin, S., Vitetta, E. S., Warnke, R. A., Kotzin, B., Schroder, J. 1979; 48: 169-195

    View details for Web of Science ID A1979JB62400008

    View details for PubMedID 121100

  • INDUCTION OF ALLOGRAFT TOLERANCE AFTER TOTAL LYMPHOID IRRADIATION (TLI) - DEVELOPMENT OF SUPPRESSOR CELLS OF THE MIXED LEUKOCYTE REACTION (MLR) JOURNAL OF IMMUNOLOGY Slavin, S., Strober, S. 1979; 123 (2): 942-946

    Abstract

    We searched for the presence of suppressor cells of the MLR in C57BL/Ka leads to BALB/c chimeras. The chimeras were made with total lymphoid irradiation (TLI) and marrow transplantation. Spleen cells from the old chimeras inhibited the MLR of BALB/c responder cells against C57BL/Ka stimulator cells. Inhibition was specific for the stimulator cells, since no effect on the MLR was observed with C3H or BALB.C3H stimulator cells. Maximal inhibition was achieved when the responder cells in the MLR shared the H-2 haplotype of the chimeric recipient. Spleen cells obtained from chimeras young 30 to 40 days after BM transplantation inhibited the MLR nonspecifically, since similar marked inhibition was observed regardless of the H-2 haplotype of the responder or stimulator cells. The finding of antigen-specific and nonspecific suppressor cells is similar to that observed in mice rendered tolerant to bovine serum albumin after treatment with TLI.

    View details for Web of Science ID A1979HD95100069

    View details for PubMedID 156766

  • MARROW TRANSPLANTATION IN MICE GIVEN TOTAL LYMPHOID IRRADIATION (TLI) - EFFECT OF THYMUS IRRADIATION, DOSE-FRACTION, AND DELAY OF CELL INFUSION Gottlieb, M., KAPLAN, H. S., Strober, S. FEDERATION AMER SOC EXP BIOL. 1979: 928–28
  • CHARACTERIZATION OF A SPONTANEOUS MURINE B-CELL LEUKEMIA (BCL1) .2. TUMOR-CELL PROLIFERATION AND IGM SECRETION AFTER STIMULATION BY LPS JOURNAL OF IMMUNOLOGY Knapp, M. R., SEVERINSONGRONOWICZ, E., Schroder, J., Strober, S. 1979; 123 (3): 1000-1006

    Abstract

    A spontaneous BALB/c B lymphocyte leukemia could be stimulated in vitro by the polyclonal B cell activator lipopolysaccharide (LPS) and the conditions for activation were studied. Spleen cells or peripheral blood lymphocytes from tumor-bearing animals responded by increased DNA synthesis and the peak of activation occurred earlier than with normal mouse spleen cells. Tumor cells harvested from the spleen, but not from the peripheral blood, could be induced by LPS to secrete IgM. Direct demonstration that the response was due to tumor cell activation and not that of contaminating normal B lymphocytes was provided by karyotype analysis and by immunoprecipitation, which showed the restriction of light chains on secreted IgM molecules to the lambda isotype.

    View details for Web of Science ID A1979HH67000006

    View details for PubMedID 381513

  • REVERSAL OF NZB-NZW DISEASE WITH TOTAL LYMPHOID IRRADIATION JOURNAL OF EXPERIMENTAL MEDICINE Kotzin, B. L., Strober, S. 1979; 150 (2): 371-378

    Abstract

    NZB/NZW mice spontaneously exhibit autoimmune disease similar to that seen in human systemic lupus erythematosus (SLE). We demonstrated that total lymphoid irradiation (TLI) reversed well expressed disease in 6-mo-old NZB/NZW females with a prolongation in survival, decrease in proteinuria, and decrease in anti-DNA antibodies as compared to control animals. Few side effects were observed in the treated group. TLI also prolonged survival in animals with advanced renal disease. These findings suggest that TLI may have application to the treatment of human SLE.

    View details for Web of Science ID A1979HF00100014

    View details for PubMedID 313431

    View details for PubMedCentralID PMC2185621

  • KARYOTYPIC DIFFERENTIATION IN A SPONTANEOUS MOUSE B-CELL LEUKEMIA CANCER GENETICS AND CYTOGENETICS Schroder, J., Suomalainen, H., Knapp, M. R., GRONOWICZ, E., Strober, S. 1979; 1 (1): 57-62
  • SURFACE IG ISOTYPES ON CELLS RESPONDING TO LIPOPOLYSACCHARIDE BY IGM AND IGG SECRETION JOURNAL OF IMMUNOLOGY SEVERINSONGRONOWICZ, E., Doss, C., Assisi, F., Vitetta, E. S., Coffman, R. L., Strober, S. 1979; 123 (5): 2049-2056

    Abstract

    Using the fluorescence-activated cell sorter (FACS), we have investigated the Ig isotypes present on murine B cells, which can be polyclonally activated by lipopolysaccharide (LPS) in low cell density cultures. The LPS response was partly inhibited as a result of staining with anti-IgD and anti-IgM reagents, but not with anti-IgG reagents. The IgM+, IgD+, or IgG- fractionated cell populations gave both an IgM and an IgG response comparable to controls, whereas the response of the IgM-, IgD- cells was 5- to 20-fold lower. IgG- cells separated 1 day after LPS stimulation could still mount an IgM and IgG response indistinguishable from controls at the peak of the response. It is concluded that IgM+, IgD+, IgG- cells constitute the major LPS-sensitive cell population in the low cell density culture system and that IgG is not a necessary cell surface isotype for precursors of IgG-secreting cells.

    View details for Web of Science ID A1979HT92000022

    View details for PubMedID 385776

  • SPONTANEOUS MURINE B-CELL LEUKEMIA Slavin, S., Weiss, L., Voss, R., Vitetta, E. S., Knapp, M. R., Strober, S. ISRAEL JOURNAL MED SCIENCES. 1979: 886–87
  • CARDIAC ALLOGRAFT SURVIVAL IN RHESUS PRIMATES TREATED WITH COMBINED TOTAL LYMPHOID IRRADIATION AND RABBIT ANTI-THYMOCYTE GLOBULIN TRANSPLANTATION BIEBER, C. P., Jamieson, S., Raney, A., Burton, N., BOGARTY, S., Hoppe, R., KAPLAN, H. S., Strober, S., Stinson, E. B. 1979; 28 (4): 347-350

    Abstract

    Eighteen abdominal heterotopic cardiac allografts were performed in outbred rhesus primates. For immunosuppression seven animals received six 100-rad/day total lymphoid irradiation (TLI) doses the week preceding transplant and three 3-mg/kg i.m. rabbit antithymocyte globulin (RATG) doses on postoperative days -1, 0, and +1; five animals were given this RATG dose but no irradiation; three were given TLI alone; and three were given no immunosuppressive therapy. Circulating T lymphocyte counts were monitored in all animals (rosettes). Graft survival in the combined TLI-RATG therapy group (169 +/- 15 days) was significantly greater than in untreated (11 +/- 1 days), RATG alone (22 +/- 12 days), or TLI alone (38 +/- 6 days) treated animals (P less than 0.001, 0.0001, and 0.001, respectively). The animals receiving combined TLI-RATG therapy also achieved significantly greater and more prolonged T lymphopenia than that obtained in the other three groups. Six of seven cardiac allografts placed in animals receiving TLI-RATG therapy were removed electively before cessation of electrical activity; however, in four of these rejection pathology was noted. Thus, it seems that combined TLI-RATG therapy may be of benefit in the management of transplant recipients, but its use will probably not abolish these patients' requirements for immunosuppressive maintenance measures.

    View details for Web of Science ID A1979HN74100017

    View details for PubMedID 116401

  • TRANSPLANTATION OF BONE-MARROW IN OUTBRED DOGS WITHOUT GRAFT VERSUS HOST DISEASE USING TOTAL LYMPHOID IRRADIATION TRANSPLANTATION Slavin, S., Gottlieb, M., Strober, S., Bieber, C., Hoppe, R., KAPLAN, H. S., GRUMET, F. C. 1979; 27 (2): 139-142

    View details for Web of Science ID A1979GN57900015

    View details for PubMedID 37616

  • PATHOLOGY AND HOMING OF A TRANSPLANTABLE MURINE B CELL LEUKEMIA (BCL1) JOURNAL OF IMMUNOLOGY Warnke, R. A., Slavin, S., Coffman, R. L., BUTCHER, E. C., Knapp, M. R., Strober, S., Weissman, I. L. 1979; 123 (3): 1181-1188

    Abstract

    The pathology and homing characteristics of a murine B cell leukemia are described. Experiments utilizing autoradiography to determine the early homing pattern of the leukemic cells revealed a pronounced localization of the labeled cells to the spleen. The cells that were seen in the white pulp showed preferential localization to the follicles or B cell domains. Tissue section immunofluorescence with antibodies to kappa- and lambda-light chains was used to study the initial mouse with this disease as well as to study the mice that were injected with in vivo passaged cells. These mice also showed predominant involvement of the spleen. Although the initial mouse with this disease had 200,000 lambda-bearing B lymphocytes per mm3 in the peripheral blood and closely resembled a human chronic lymphocytic leukemia patient, the studies described suggest that this murine B cell neoplasm is a lymphoma with a striking predilection for splenic involvement. The other organs including the bone marrow as well as the peripheral blood appeared to be involved secondarily. This unusual spontaneously occurring murine B cell disease provides a useful model for the investigation of certain commonly occurring human lymphomas and leukemias.

    View details for Web of Science ID A1979HH67000037

    View details for PubMedID 381519

  • ARTHRITIS IN A PATIENT WITH MYCOSIS-FUNGOIDES - COMPLETE REMISSION AFTER RADIOTHERAPY ARTHRITIS AND RHEUMATISM Gottlieb, M., Hoppe, R. T., Calin, A., Strober, S. 1979; 22 (4): 424-425

    View details for Web of Science ID A1979GR36900019

    View details for PubMedID 106860

  • TREATMENT OF RHEUMATOID-ARTHRITIS WITH REGIONAL LYMPHOID IRRADIATION Kotzin, B. L., Strober, S., Slavin, S., Gottlieb, M., Calin, A., Fries, J., Hoppe, R., KAPLAN, H. S. LIPPINCOTT-RAVEN PUBL. 1979: 632–32
  • TRANSPLANTATION TOLERANCE AFTER TOTAL LYMPHOID IRRADIATION TRANSPLANTATION PROCEEDINGS Strober, S., Slavin, S., Fuks, Z., KAPLAN, H. S., Gottlieb, M., Bieber, C., Hoppe, R. T., GRUMET, F. C. 1979; 11 (1): 1032-1038

    View details for Web of Science ID A1979GQ02500226

    View details for PubMedID 377606

  • ALLOGRAFT TOLERANCE AFTER TOTAL LYMPHOID IRRADIATION (TLI) IMMUNOLOGICAL REVIEWS Strober, S., Slavin, S., Gottlieb, M., ZANBAR, I., King, D. P., Hoppe, R. T., Fuks, Z., GRUMET, F. C., KAPLAN, H. S. 1979; 46: 87-112

    View details for Web of Science ID A1979HG24000004

    View details for PubMedID 39027

  • CELL-DIFFERENTIATION IN THE PRESENCE OF CYTOCHALASIN-B - STUDIES ON THE SWITCH TO IGG SECRETION AFTER POLYCLONAL-B CELL ACTIVATION JOURNAL OF IMMUNOLOGY VANDERLOO, W., GRONOWICZ, E. S., Strober, S., Herzenberg, L. A. 1979; 122 (4): 1203-1208

    Abstract

    Mouse spleen cells were cultured with lipopolysaccharide in conditions that activate both IgM and IgG secretion. Addition of cytochalasin B (CB), an inhibitor of cytokinesis, lead to a high degree of polynucleation, with little effect on Ig secretion. Using cytoplasmic staining with fluorochrome conjugated antisera, we determined the numbers of IgG-containing cells that also contained IgM in their cytoplasm. Such double staining cells were relatively more frequent at early times of the cultures, but at all times single producing cells were in the majority. Addition of CB over the period when the IgG producing cells first appear, lead to a marked increased frequency of double staining, polynucleated cells. This characteristic was stable over a period of at least 42 hr, suggesting that each double staining cell actively synthesized both isotypes. When CB was added after IgG production had started, little increase in the numbers of double staining cells were observed, although polynucleation remained extensive. These data confirm previous findings that the lineage of one cell can produce both IgM and IgG. Furthermore, the results suggest that cells in the process of switching from IgM to IgG go through an asymmetric division leading to one IgM-producing and one IgG-producing daughter cell.

    View details for Web of Science ID A1979GQ35500006

    View details for PubMedID 376713

  • CARDIAC ALLOGRAFT SURVIVAL IN RHESUS PRIMATES TREATED WITH TOTAL LYMPHOID IRRADIATION AND RABBIT ANTI-THYMOCYTE GLOBULIN SURGICAL FORUM BIEBER, C. P., Jamieson, S. W., Raney, A., Burton, N. A., BOGARTY, S., Hoppe, R., KAPLAN, H. S., Strober, S., Stinson, E. B. 1979; 30: 284-286

    View details for Web of Science ID A1979JB37300125

    View details for PubMedID 120018

  • Cellular basis of tolerance to serum albumin in adult mice. I. characterization of T suppressor and T helper cells. Journal of immunology (Baltimore, Md. : 1950) Zan-Bar, I., Murphy, D. B., Strober, S. 1978; 120 (2): 497–506

    Abstract

    The surface markers and size of suppressor cells were determined in adult (BALB/c x C57BL/Ka)F1 mice which were tolerized with a single injection of deaggregated bovine serum albumin (BSA). Suppressor cells from the spleens of tolerazided donors were assayed in a cell transfer system in which graded numbers of cells were injected into irradiated syngeneic mice along with limiting numbers of T cells primed to BSA and an excess of B cells primed to DNP-BSA. Adoptive hosts were challenged with DNP-BSA in saline, and the anti-DNP response was measured. Suppressor cells were antigen specific as shown by the inhibitory activity of BSA-tolerant spleen cells on the response to DNP-BSA, but not to DNP-BGG. Suppressor cells were eliminated by in vitro treatment with anti-Thy 1.2, anti-Ly-2.2, anti-I-J subregion antisera and C, but not with anti-Ly-1 or anti-I-A subregion antisera. Neither unprimed nor primed helper T cells were detected in the spleen of tolerized donors after in vitro treatment with anti-Ly-2.2 antisera. Both helper and suppressor T cells from the spleens of primed or tolerized donors, respectively, showed a rapid sedimentation velocity (S greater than 3.7 mm/hr).

    View details for PubMedID 74390

  • INDUCTION AND MECHANISM OF TOLERANCE TO BOVINE SERUM-ALBUMIN IN MICE GIVEN TOTAL LYMPHOID IRRADIATION (TLI) JOURNAL OF IMMUNOLOGY ZANBAR, I., Slavin, S., Strober, S. 1978; 121 (4): 1400-1404

    Abstract

    BALB/c mice given total lymphoid irradiations (TLI) were injected i.p. with bovine serum albumin (BSA) in saline, and challenged with DNP-BSA in complete Freund's adjuvant 6 weeks later. The latter animals made no anti-DNP antibody response as measured by a modified Farr assay, but made a normal anti-DNP response after challenge with DNP-BGG in adjuvant. Normal mice or mice given whole body irradiation were not tolerized by the i.p. injection of BSA in saline. Spleen cells from unresponsive mice (TLI + BSA in saline) suppressed the adoptive secondary anti-DNP response of sublethally irradiated syngeneic hosts given BSA-primed T cells, DNP-BSA-primed B cells, and DNP-BSA in saline. The suppressor cells were antigen specific, and were inactivated by in vitro treatment with anti-Thy 1.2 antiserum and complement. The findings suggest that soluble antigens administered to mice after TLI evoke a state of tolerance that is maintained by antigen-specific suppressor T cells. A similar mechanism may be involved in the maintenance of tolerance to allografts. These findings may have important clinical implications for patients treated with TLI for lymphoid malignancies.

    View details for Web of Science ID A1978FS42000030

    View details for PubMedID 81232

  • ALLOGENEIC BONE-MARROW TRANSPLANTATION IN OUTBRED DOGS USING TOTAL LYMPHOID IRRADIATION SLAVIN, S., BIEBER, C. P., HOPPE, R. T., GRUMET, C. F., KAPLAN, H. S., STROBER, S. SLACK INC. 1978: A385
  • SPONTANEOUS MURINE-B CELL LEUKEMIA (MBL1) - ANIMAL-MODEL FOR HUMAN CHRONIC LYMPHOCYTIC-LEUKEMIA SLAVIN, S., KNAPP, M. R., JONES, P. P., STROBER, S. FEDERATION AMER SOC EXP BIOL. 1978: 1451
  • CHARACTERIZATION OF SUPPRESSOR T-CELLS IN TOLERANT MICE ZANBAR, STROBER, S. GUSTAV FISCHER VERLAG. 1978: 379
  • RELATIONSHIP BETWEEN SURFACE-IMMUNOGLOBULIN ISOTYPE AND IMMUNE FUNCTION OF MURINE-B LYMPHOCYTES .3. EXPRESSION OF A SINGLE PREDOMINANT ISOTYPE ON PRIMED AND UNPRIMED B-CELLS JOURNAL OF EXPERIMENTAL MEDICINE ZANBAR, I., Vitetta, E. S., Assisi, F., Strober, S. 1978; 147 (5): 1374-1394

    Abstract

    We determined whether primed and unprimed B cells in the spleen of (BALB/c x C57BL/Ka)F(1) mice contain subpopulations that express a predominant surface Ig isotype. Spleen cells were stained for surface isotypes and sorted on the fluorescence-activated cell sorter (FACS) in order to obtain B cells bearing predominantly IgM (mup cells), IgD (deltap cells), or IgG (gammap cells). Each population was assayed for its capacity to restore the adoptive primary and secondary anti-bovine serum albumin (BSA) antibody response in irradiated syngeneic recipients. In addition, the adoptive response restored by isotype-predominant cells was compared to that restored by isotype- positive cells (B cells bearing a given surface isotype alone or in combination with others). The experimental results show that mup cells restore the adoptive primary and secondary IgM and IgG responses to BSA, and gammaP cells restore only the primary and secondary IgG response. Deltap Cells restored the adoptive secondary IgG response, but failed to restore the adoptive primary response at the cell doses tested. GammaP Cells but not deltap cells suppressed the IgM response of the mu(+) and delta(+) cells. The contribution of isotype-predominant cells to both the adoptive primary and secondary anti-BSA response was smaller than that of B cells bearing a combination of surface isotypes. Differences in the Ig isotype pattern expressed on the surface of primed and unprimed B cells are discussed.

    View details for Web of Science ID A1978EX58100008

    View details for PubMedID 306414

    View details for PubMedCentralID PMC2184263

  • SPONTANEOUS MURINE B-CELL LEUKEMIA NATURE Slavin, S., Strober, S. 1978; 272 (5654): 624-626

    View details for Web of Science ID A1978EU45600039

    View details for PubMedID 306069

  • TRANSPLANTATION OF ALLOGENEIC BONE-MARROW WITHOUT GRAFT VERSUS HOST DISEASE USING TOTAL LYMPHOID IRRADIATION JOURNAL OF EXPERIMENTAL MEDICINE Slavin, S., Fuks, Z., KAPLAN, H. S., Strober, S. 1978; 147 (4): 963-972

    Abstract

    Bone marrow (BM) and skin allografts from C57BL/Ka (H-2b/b) mice were transplanted to BALB/c (H-2d/d) recipients treated with total lymphoid irradiation (TLI), whole-body irradiation (WBI), or fractionated thymic irradiation TLI prolonged skin allograft survival about five times as long as that in untreated controls, and allowed for permanent engraftment of BM cells in approximately equal to 90% of recipients. None of the BM recipients showed clinical signs of graft-versus-host disease (GVHD) (diarrhea, weight loss, hunched back, etc.). On the other hand, recipients given WBI and allogeneic BM cells developed severe clinical GVHD. The majority of the latter recipients died within 12 days after BM transplantation, and 95% died within 61 days. Although TLI protected BALB/c mice against GVHD induced by BM cells, all recipients given TLI and allogeneic spleen cells developed lethal GVHD. Thymic irradiation alone marginally prolonged skin allograft survival, and did not allow for allogeneic BM engraftment. These results suggest that TLI may be a useful regimen in clinical BM transplantation, since this form of radiotherapy is used extensively in humans and has few severe side effects.

    View details for Web of Science ID A1978ET46700001

    View details for PubMedID 25942

    View details for PubMedCentralID PMC2184246

  • LONG-TERM EFFECTS OF RADIATION ON T-LYMPHOCYTES AND B-LYMPHOCYTES IN PERIPHERAL-BLOOD AFTER REGIONAL IRRADIATION CANCER Hoppe, R. T., Fuks, Z. Y., Strober, S., KAPLAN, H. S. 1977; 40 (5): 2071-2078

    Abstract

    The long term alterations of T and B lymphocytes in the peripheral blood of patients treated with regional irradiation for various malignancies were examined. Eighty patients were tested at various intervals after the completion of irradiation. Absolute lymphocyte counts, the percentages of T cells and B cells, and the blastogenic response to phocyte reaction (MLR) were determined. Nearly all patients initially had absolute lymphocytopenia and one-third of the patients tested 3 years after completion of irradiation had lymphocyte counts which were more than two standard deviations below the normal range. The depression was not specific for either the T-or B-lymphocyte subpopulations. The PHA response was impaired for extended periods of time after the completion or irradiation. Differences in the mean response of lymphocytes to PHA were noted for all concentrations of the mitogen, but were most marked with suboptimal concentrations of PHA. The MLR was below the lower limits of normal in 70% of the recently irradiated patients. There was a gradual recovery of the ability to respond in the MLR, and all patients tested more than 4.5 years after the completion of therapy had a normal response. These results were compared with those obtained in patients treated with total lymphoid irradiation for Hodgkin's disease. Although three appeared to be a difference in the effect of radiation on lymphocyte subpopulations in the two groups, the effects on lymphocyte function were similar.

    View details for Web of Science ID A1977EC72600012

    View details for PubMedID 144554

  • T-CELLS AND B-CELLS IN IMMUNOLOGICAL DISEASES AMERICAN JOURNAL OF CLINICAL PATHOLOGY STROBER, S. 1977; 68 (5): 671–78
  • FUNCTIONAL CHARACTERISTICS OF B-CELLS SORTED FOR SURFACE IGM, IGG OR IGD ZANBAR, STROBER, S., VITETTA, E. S. FEDERATION AMER SOC EXP BIOL. 1977: 1316
  • BONE-MARROW TRANSPLANTATION ACROSS MAJOR HISTOCOMPATIBILITY BARRIERS IN MICE TREATED WITH FRACTIONATED TOTAL LYMPHOID IRRADIATION SLAVIN, S., STROBER, S., FUKS, Z., KAPLAN, H. S. FEDERATION AMER SOC EXP BIOL. 1977: 1226
  • CHARACTERIZATION OF SUPPRESSOR T-CELLS IN TOLERANT MICE ZANBAR, STROBER, S. WILEY-LISS. 1977: 190
  • SERUM FACTORS AND T-LYMPHOCYTES IN HODGKINS-DISEASE - CORRECTION - REPLY NEW ENGLAND JOURNAL OF MEDICINE STROBER, S. 1977; 296 (11): 630
  • RESPONSE PATTERN OF B CELLS AFTER POLYCLONAL ACTIVATION GRONOWICZ, E., STROBER, S., VANDERLOO, W. WILEY-LISS. 1977: 216
  • BONE-MARROW AND ORGAN-TRANSPLANTATION FOLLOWING TOTAL LYMPHOID IRRADIATION IN RODENTS SLAVIN, S., REITZ, B. A., STROBER, S., BIEBER, C. P., KAPLAN, H. S. SLACK INC. 1977: A348
  • CHARACTERIZATION OF B CELL SUBPOPULATIONS BY VELOCITY SEDIMENTATION, SURFACE LA ANTIGENS AND IMMUNE FUNCTION EUROPEAN JOURNAL OF IMMUNOLOGY Press, J. L., Strober, S., Klinman, N. R. 1977; 7 (6): 329-335

    View details for Web of Science ID A1977DQ03200001

    View details for PubMedID 302204

  • TOTAL LYMPHOID IRRADIATION IN TISSUE TRANSPLANTATION IN MICE TRANSPLANTATION PROCEEDINGS Slavin, S., Strober, S., Fuks, Z., KAPLAN, H. S. 1977; 9 (1): 1001-1004

    View details for Web of Science ID A1977DA33000205

    View details for PubMedID 141119

  • RELATIONSHIP BETWEEN SURFACE-IMMUNOGLOBULIN ISOTYPE AND IMMUNE FUNCTION OF MURINE B LYMPHOCYTES .2. SURFACE-IMMUNOGLOBULIN ISOTOPES ON UNPRIMED B CELLS IN SPLEEN JOURNAL OF EXPERIMENTAL MEDICINE ZANBAR, I., Vitetta, E. S., Strober, S. 1977; 145 (5): 1206-1215

    Abstract

    We investigated the ability of IgM-, IgD-, and IgG-bearing cells from the spleens of unprimed (BALB/c x C57BL/Ka)F1 mice to restore the adoptive primary anti-BSA and anti-DNP antibody responses. Purified populations of isotype-specific cells were prepared by immunofluorescent staining and sorting on the fluorescence activated cell sorter. Bright or dull cells were transferred to irradiated syngeneic recipients which were challenged with DNP-BSA in complete Freund's adjuvant. Unfractionated spleen cells as well as IgM- and IgD-bearing cells restored the adoptive primary IgM and IgG antibody response. IgG-bearing cells restored a vigorous adoptive response which was all IgG (2-mercaptoethanol resistant). Depletion of IgG-bearing cells markedly increased the adoptive IgM response, and depletion of IgM-bearing cells markedly increased the IgG response. However, depletion of IgD-bearing cells resulted in a considerable reduction in the IgG response. The latter finding indicates that there is a subpopulation of IgD-bearing cells which express little or no surface IgM and which make a considerable contribution to the adoptive primary IgG response.

    View details for Web of Science ID A1977DE62900009

    View details for PubMedID 323403

    View details for PubMedCentralID PMC2180673

  • RELATIONSHIP BETWEEN SURFACE-IMMUNOGLOBULIN ISOTYPE AND IMMUNE FUNCTION OF MURINE B LYMPHOCYTES .1. SURFACE-IMMUNOGLOBULIN ISOTYPES ON PRIMED B CELLS IN SPLEEN JOURNAL OF EXPERIMENTAL MEDICINE ZANBAR, I., Strober, S., Vitetta, E. S. 1977; 145 (5): 1188-1205

    Abstract

    We investigated the ability of IgM-, IgD-, and IgG-bearing cells from the spleens of (BALB/c x C57BL/Ka)F1 mice primed to dinitrophenyl-bovine serum albumin (DNP-BSA) to restore the adoptive secondary anti-BSA and anti-DNP antibody responses. A rabbit anti-mouse IgD antiserum was prepared and the specificity documented by radioimmunoprecipitation, and cell surface staining. Purified populations of IgM-, IgD-, and IgG-bearing cells were prepared by immunofluorescent staining with isotype-specific reagents, and sorting on the fluorescence activated cell sorter. Bright or dull cells were transferred to irradiated syngeneic recipients which were challenged with DNP-BSA in saline. Unfractionated spleen cells restored an adoptive secondary serum antibody response which was all IgG (2-mercaptoethanol resistant). Purified IgM- or IgD-bearing cells restored both the secondary IgM and IgG antibody response. IgG-bearing cells restored only the IgG response. In addition, the IgG-bearing cells appear to suppress the adoptive secondary IgM response, since depletion of IgG-bearing cells from transferred spleen cells results in a marked increase in the adoptive IgM response.

    View details for Web of Science ID A1977DE62900008

    View details for PubMedID 323402

    View details for PubMedCentralID PMC2180668

  • INDUCTION OF SPECIFIC TISSUE TRANSPLANTATION TOLERANCE USING FRACTIONATED TOTAL LYMPHOID IRRADIATION IN ADULT MICE - LONG-TERM SURVIVAL OF ALLOGENEIC BONE-MARROW AND SKIN-GRAFTS JOURNAL OF EXPERIMENTAL MEDICINE Slavin, S., Strober, S., Fuks, Z., KAPLAN, H. S. 1977; 146 (1): 34-48

    Abstract

    BALB/c mice were treated with fractionated high dose (3,400 rads) total lymphoid irradiation (TLI), and given semiallogeneic (BALB/c x C57BL/Ka) or allogeneic (C57BL/Ka) bone marrow and/or skin allografts. TLI alone prolonged the mean survival time (m.s.t.) of C57BL/Ka skin grafts to 49.1 days (control, 10.7 days). Shielding of the thymus during TLI produced only a slight increase in graft survival (m.s.t., 19 days). TLI combined with splenectomy was no more effective than TLI alone. Infusion of 10(7) semiallogeneic or allogeneic bone marrow cells after TLI produced stable chimeras in 7/8 and 8/15 recipients, respectively. Chimeras were specifically tolerant to donor tissues, since C57BL/Ka skin grafts were accepted for more than 250 days, but third-party (C3H/He) skin grafts were rejected rapidly. In addition, chimeric lymphocytes responded to C3H/He and C3H. Q but not to C57BL/Ka cells in the one-way mixed leukocyte reactions. BALB/c C57BL/Ka chimeras showed no clinical evidence of graft vs. host disease. These findings may have application of clinical organ transplantation, since (a) the recipient treatment (TLI) has already been shown to be safe in humans, (b) donors and recipients can be completely allogeneic, and (c) bone marrow and skin graft survival was permanent (greater than 250 days).

    View details for Web of Science ID A1977DL29800004

    View details for PubMedID 17647

    View details for PubMedCentralID PMC2180728

  • CELLULAR BASIS OF TOLERANCE TO SERUM-ALBUMIN IN ADULT MICE .1. CHARACTERIZATION OF T-SUPPRESSOR AND T-HELPER CELLS JOURNAL OF IMMUNOLOGY ZANBAR, I., Murphy, D. B., Strober, S. 1977; 120 (2): 497-506
  • LONG-TERM SURVIVAL OF SKIN ALLOGRAFTS IN MICE TREATED WITH FRACTIONATED TOTAL LYMPHOID IRRADIATION SCIENCE Slavin, S., Strober, S., Fuks, Z., KAPLAN, H. S. 1976; 193 (4259): 1252-1254

    Abstract

    Treatment of recipient Balb/c mice with fractionated, high-dose total lymphoid irradiation, a procedure commonly used in the therapy of human malignant lymphomas, resulted in fivefold prolongation of the survival of C57BL/Ka skin allografts despite major histocompatibility differences between the strains (H-2d and H-2b, respectively). Infusion of 10(7) (C57BL/Ka x Balb/c)F1 bone marrow cells after total lymphoid irradiation further prolonged C57BL/Ka skin graft survival to more than 120 days. Total lymphoid irradiation may eventually prove useful in clinical organ transplantation.

    View details for Web of Science ID A1976CD84600022

    View details for PubMedID 785599

  • LONG-TERM EFFECTS OF RADIATION ON IMMUNE FUNCTION IN PATIENTS WITH HODGKINS-DISEASE STROBER, S., SASSAZUKI, T., MCMICHAEL, A., FUKS, Z., KAPLAN, H. S. SLACK INC. 1976: A151
  • MATURATION OF B-LYMPHOCYTES IN RATS .3. 2 SUBPOPULATIONS OF MEMORY-B CELLS IN THORACIC-DUCT LYMPH DIFFER BY SIZE, TURNOVER RATE, AND SURFACE-IMMUNOGLOBULIN JOURNAL OF IMMUNOLOGY STROBER, S. 1976; 117 (4): 1288–94

    Abstract

    We examined the ability of large and small thoracic duct cells obtained from Lewis rats primed to DNP to restore the adoptive secondary anti-DNP response in irradiated syngeneic hosts given an excess of T helper cells. The large cells were four to five times more active on a per cell basis than were the small cells. However, the large cells constitute only 7 to 8% of the thoracic duct cells and, therefore, make a minor contribution to the restorative activity of the unfractionated cells. Pretreatment of thoracic duct cell donors with high specific activity 3H-TdR for 48 hr before cannulation markedly reduced the memory B cell activity of the large cells, but had little effect on that of small cells. In addition, the activity of the large cells diminished with time after primary immunization, but that of the small cells remained stable. Immunofluorescent staining of the large and small cells for surface IgM and IgG, and subsequent sorting on the fluorescence-activated cell sorter (FA CS), showed that surface IgM was present on large memory B cells, and that IgG was present on small memory B cells. The experimental results suggest that two subpopulations of memory B cells in the thoracic duct lymph differ by size, rate of turnover, persistence after primary immunization, and class of surface IgG.

    View details for Web of Science ID A1976CK18000035

    View details for PubMedID 1086321

  • DELINEATION OF PRIMARY B-CELL SUBPOPULATIONS BY SIZE FRACTIONATION PRESS, J. L., STROBER, S., KLINMAN, N. R. FEDERATION AMER SOC EXP BIOL. 1976: 245
  • LONG-TERM SKIN ALLOGRAFT SURVIVAL AFTER FRACTIONATED TOTAL LYMPHOID IRRADIATION IN MICE SLAVIN, S., STROBER, S., FUKS, Z., KAPLAN, H. S. FEDERATION AMER SOC EXP BIOL. 1976: 334
  • LONG-TERM EFFECTS OF RADIATION ON T AND B LYMPHOCYTES IN PERIPHERAL-BLOOD OF PATIENTS WITH HODGKINS-DISEASE Fuks, Z., Strober, S., BOBROVE, A., KAPLAN, H. S. SLACK INC. 1976: A150–A150
  • INTERACTION BETWEEN SERUM FACTORS AND T-LYMPHOCYTES IN HODGKINS-DISEASE - USE AS A DIAGNOSTIC TEST NEW ENGLAND JOURNAL OF MEDICINE Fuks, Z., Strober, S., KAPLAN, H. S. 1976; 295 (23): 1273-1278

    Abstract

    We studied the mechanism of defective binding of sheep erythrocytes to the surface of peripheral blood T lymphocytes (E-rosette-formation) in Hodgkin's disease. The decreased percentage of E-rosette-forming cells (range, 21 to 77 per cent) in 25 patients with Hodgkin's disease was reversed and returned to normal range (52 to 78 per cent) by prior incubation of the T lymphocytes in tissue-culture medium with 20 per cent fetal-calf serum for 18 to 24 hours. The percentage of E-rosette-forming cells was suppressed by additional incubation with serum from patients with Hodgkin's disease (range, 20 to 61 per cent) but not with serum from patients with other neoplasms or from normal subjects (range, 52 to 74 per cent). Only target T lymphocytes from patients with Hodgkin's disease were suppressed by Hodgkin-disease serum. The findings suggest that there is a specific interaction between serum factors and the surface of peripheral blood T lymphocytes in Hodgkin's disease.

    View details for Web of Science ID A1976CM59200001

    View details for PubMedID 185517

  • ALTERATIONS IN T AND B LYMPHOCYTES IN HEART-TRANSPLANT PATIENTS EARLY AND LATE POSTOPERATIVELY JOURNAL OF CLINICAL INVESTIGATION KHALAF, T. H., Strober, S., GARRELTS, G., Stinson, E. B. 1976; 58 (1): 212-220

    Abstract

    Alterations in the percent and absolute number of thymus-derived (T) and bursa-equivalent (B) lymphocytes in peripheral blood were followed in 10 patients treated with antithymocyte globulin, prednisone, and azathioprine after cardiac transplantation. During the 1st postoperative wk the percent of T cells dropped below 10% in almost all cases (normal range, 65-91%) with a concomitant rise in the percent of B cells. However, the absolute T- and B-cell counts were both markedly depressed (less than 200 cells/mm3). During the 7-wk postoperative period the percent of T cells rose to 45-60% and the absolute count rose from 100 to 350 cells/mm3 (normal range, 1,092-2,400 cells/mm3). Although the percent of B cells was elevated (35-50%) during this period, the absolute B-cell count remained below the range of normals (268-640 cells/mm3). Follow-up of long-term survivors (3-60 mo postoperative) showed a continued marked T (467 cells/mm3) and B (95 cells/mm3) lymphocytopenia. Chronological relationships between the percent and absolute T-cell count and episodes of graft rejection in individual patients are discussed as possible adjuncts in the prediction of rejection crises.

    View details for Web of Science ID A1976BW87100025

    View details for PubMedID 777028

    View details for PubMedCentralID PMC333172

  • LONG-TERM EFFECTS OF RADIATION ON T-LYMPHOCYTES AND B-LYMPHOCYTES IN PERIPHERAL-BLOOD OF PATIENTS WITH HODGKINS-DISEASE JOURNAL OF CLINICAL INVESTIGATION Fuks, Z., Strober, S., Bobrove, A. M., Sasazuki, T., McMichael, A., KAPLAN, H. S. 1976; 58 (4): 803-814

    Abstract

    Total lymphocyte counts, and the percentage of T and B lymphocytes and monocytes in untreated patients with Hodgkin's disease were not significantly different from those observed in normal donors. At the completion of radiotherapy, the mean total lymphocyte count of 503/mm3 was 4 SD below the mean for normal controls. Although a group of 26 patients in continuous complete remission from 12 to 111 mo after radiation treatment regained normal total numbers of lymphocytes and monocytes, they exhibited a striking T lymphocytopenia and B lymphocytosis. Concomitantly, there was a significant increase of null (neither T nor B) lymphocytes. The response of peripheral blood lymphocytes to phytohemagglutinin, concanavalin A, and tetanus toxoid before treatment was significantly impaired. 1-10 yr after completion of treatment there seemed to be little or no recovery of these responses. The capacity of peripheral blood lymphocytes to respond to allo-antigens on foreign lymphocytes in vitro (mixed lymphocyte reaction) was normal in nine untreated patients. However, the mixed lymphocyte reaction was markedly impaired during the first 2 yr after treatment. There was a partial and progressive restoration of the mixed lymphocyte reaction during the next 3 yr, and normal responses were observed in patients in continuous complete remission for 5 yr or more. The in vivo response to dinitrochlorobenzene was also examined. 88% (15/17) of patients initially sensitive to dinitrochlorobenzene were anergic to the allergen at the completion of a course of radiotherapy, but nine of these regained their hypersensitivity response during the 1st yr after treatment. This data suggests that there is a sustained alteration in both the number and function of circulating T cells after radiation therapy in patients with Hodgkin's disease which may persist for as long as 10 yr after treatment. The restoration of cell mediated immune functions after radiotherapy is time dependent and its kinetics may differ for various T-cell functions. The implications of these findings with respect to the state of immunological competence after radiotherapy are discussed.

    View details for Web of Science ID A1976CG61400006

    View details for PubMedID 135001

    View details for PubMedCentralID PMC333242

  • REVERSAL OF CELL-SURFACE ABNORMALITIES OF T LYMPHOCYTES IN HODGKINS-DISEASE AFTER INVITRO INCUBATION IN FETAL SERA JOURNAL OF IMMUNOLOGY Fuks, Z., Strober, S., King, D. P., KAPLAN, H. S. 1976; 117 (4): 1331-1335

    Abstract

    The capacity of periphal blood lymphocytes from patients with untreated Hodgkin's disease to form E rosettes with sheep erythrocytes and to respond in vitro to PHA stimulation were found to be profoundly impaired. In 49% of the patients, the percentage of E rosette-forming cells (E-RFC) was more than two standard deviations below the mean for normal donors. Overnight incubation of the peripheral blood lymhocytes from these patients in culture media containing 20% fetal calf serum was followed by restoration of the percentage of E-RFC up to normal levels. Similar results have been observed after incubation in fetal human serum, but not in adult human AB serum or adult bovine serum. Incubation of peripheral blood lymphocytes from untreated patients in20% fetal calf serum also resulted in a remarkable restoration of their capacity to respond normally to PHA. Possible mechanisms involved in these reversible cell surface and in vitro lymphocyte function abnormalities in Hodgkin's disease are discussed.

    View details for Web of Science ID A1976CK18000043

    View details for PubMedID 1086325

  • QUANTITATION OF T-LYMPHOCYTES AND B-LYMPHOCYTES AND CELLULAR IMMUNE FUNCTION IN HODGKINS-DISEASE CANCER Bobrove, A. M., Fuks, Z., Strober, S., KAPLAN, H. S. 1975; 36 (1): 169-179

    Abstract

    Peripheral blood T and B lymphocytes were quantitated in 42 patients with untreated Hodgkin's disease and the results compared with the response to phytohemagglutinin (PHA) stimulation and delayed hypersensitivity skin testing. T lymphocytes were identified by an in vitro cytotoxicity assay employing a specific anti-T-cell serum and by spontaneous rosette formation with sheep erythrocytes (E rosettes). The percentage of T cells in the patients was similar to that of normal subjects as judged by the cytotoxicity assay (65 to 90%). In addition, absolute T-lymphocyte counts were normal in 63% of the patients and were generally reduced only in those with lymphopenia. The percentage of T lymphocytes determined by the E-rosette assay was similar to that determined by the cytotoxicity assay in normal controls, but was significantly lower than that determined by the cytotoxicity assay in the patients. Moreover, the decreased response to PHA stimulation in the patients was directly correlated with the decrease in E-rosette formation. These findings suggest that T lymphocytes in the peripheral blood are not generally diminished in untreated Hodgkin's disease. However, a proportion of these cells exhibits altered surface interactions that may account for some aspects of their impaired immunologic function.

    View details for Web of Science ID A1975AK56600014

    View details for PubMedID 54208

  • IMMUNE FUNCTION CELL-SURFACE CHARACTERISTICS AND MATURATION OF B-CELL SUBPOPULATIONS TRANSPLANTATION REVIEWS STROBER, S. 1975; 24: 84–112

    View details for Web of Science ID A1975AH93100003

    View details for PubMedID 49963

  • MATURATION OF B-LYMPHOCYTES IN RAT .2. SUBPOPULATIONS OF VIRGIN B-LYMPHOCYTES IN SPLEEN AND THORACIC-DUCT LYMPH JOURNAL OF IMMUNOLOGY STROBER, S. 1975; 114 (2): 877–85

    Abstract

    Thoracic duct and spleen cells of normal (unimmunized) adult rats were fractionated according to size by 1 times G velocity sedimentation. Fractions were tested for their ability to restore the adoptive antibody response of irradiated hosts to horse spleen ferritin. A constant source of T cells (small numbers of unfractionated thoracic duct cells) was added to each fraction in order to monitor the B cell activity of the latter. Although large and small cell fractions of the spleen showed restorative activity, only the small cell fractions of the thoracic duct lymph showed activity. The turnover rate of the spleen cell fractions was determined by treating donors with high specific-activity 3H-thymidine for 48 hr before splenectomy. Rapidly dividing cells are preferentially killed by this treatment. The results suggest that a considerable proportion of large, intermediate, and small virgin B cells turn over within 48 hr. The cell surface of the various spleen cell fractions was examined for the presence of immunoglobulin (Ig) and a receptor for complement. The percentage of Ig-bearing cells in the large cell fractions was similar to the percentage of cells bearing IgM and a receptor for complement. However, the majority of Ig-bearing cells in the small cell fractions did not show the latter two surface markers. Experiments with the fluorescence-activated cell sorter showed that the large functionally active B cells bore surface IgM. The experimental findings suggest that there are subpopulations of virgin B cells in the spleen of the adult rat which differ with respect to size, migration pattern, turnover rate, and cell surface characteristics. The relationship of these cells to one another is discussed in the framework of an antigen-independent model of B cell maturation in the rat.

    View details for Web of Science ID A1975V710800029

    View details for PubMedID 46256

  • SUBPOPULATIONS OF B-LYMPHOCYTES IN SPLEEN, LYMPH AND MARROW OF RATS STROBER, S. FEDERATION AMER SOC EXP BIOL. 1975: 995
  • IMMUNE SPECIFIC PRODUCTION OF INTERFERON BY HUMAN T-CELLS IN COMBINED MACROPHAGE-LYMPHOCYTE CULTURES IN RESPONSE TO HERPES-SIMPLEX ANTIGEN JOURNAL OF IMMUNOLOGY Valle, M. J., Bobrove, A. M., Strober, S., Merigan, T. C. 1975; 114 (1): 435-441

    Abstract

    Human peripheral blood lymphocytes, highly enriched for T cells, were obtained by passing gravity-sedimented leukocytes through nylon wool columns. The eluted cells were cultured with autologous macrophages and the mixture was studied for its capacity to produce interferon in vitro in response to stimulation with herpes simplex virus antigen. The interferon produced by the combined macrophage-lymphocyte cultures was shown to depend upon the presence of T cells; elimination of these cells by treatment with an anti-T cell serum plus complement greatly diminished the amount of interferon produced. The memory for the immune-specific release of interferon also appeared to be carried by the T lymphocytes rather than the glass-adherent macrophages. Furthermore, the results suggest that under our conditions of culture immune-specific interferon originates from T cells.

    View details for Web of Science ID A1975W269900035

    View details for PubMedID 46881

  • T AND B CELLS IN HODGKINS-DISEASE - REPLY NEW ENGLAND JOURNAL OF MEDICINE KAPLAN, H. S., Bobrove, A. M., Fuks, Z., Strober, S. 1974; 290 (17): 971-971
  • IDENTIFICATION AND QUANTITATION OF THYMUS-DERIVED LYMPHOCYTES IN HUMAN PERIPHERAL-BLOOD JOURNAL OF IMMUNOLOGY Bobrove, A. M., Strober, S., HERZENBE, L. A., DEPAMPHI, J. D. 1974; 112 (2): 520-527

    View details for Web of Science ID A1974S040600011

    View details for PubMedID 4130690

  • SPONTANEOUS SHEEP RED BLOOD-CELL (SRBC) ROSETTE FORMATION AND MITOGEN RESPONSIVENESS OF HUMAN T LYMPHOCYTES Bobrove, A. M., Strober, S., Fuks, Z., KAPLAN, H. S. FEDERATION AMER SOC EXP BIOL. 1974: 742–42
  • MATURATION OF B LYMPHOCYTES IN RAT .1. MIGRATION PATTERN, TISSUE DISTRIBUTION, AND TURNOVER RATE OF UNPRIMED AND PRIMED B LYMPHOCYTES INVOLVED IN ADOPTIVE ANTIDINITROPHENYL RESPONSE JOURNAL OF EXPERIMENTAL MEDICINE STROBER, S., DILLEY, J. 1973; 138 (6): 1331–44

    Abstract

    The migration pattern, tissue distribution, and turnover rate of unprimed and primed B lymphocytes involved in the adoptive anti-DNP response was studied. The adoptive primary response restored by unprimed spleen or thoracic duct cells passaged through an intermediate host (intravenous injection and subsequent collection in the thoracic duct lymph) was markedly diminished as compared with that restored by unpassaged cells. On the other hand, the adoptive response restored by passaged spleen or thoracic duct cells from DNP-primed donors was greater than or the same as that restored with unpassaged cells, respectively. This suggests that unprimed B cells change from nonrecirculating to recirculating lymphocytes after exposure to antigen. Studies of the adoptive anti-DNP response restored by unprimed or primed bone marrow cells showed little change in the time-course or amplitude of the response restored by either population of cells. The relative inability of marrow cells to carry immunological memory was related to the inability of recirculating memory cells to penetrate the marrow. The turnover rate of unprimed and primed B cells was investigated by treating the cell donors with [(3)H]thymidine for 48 h before removal of thoracic duct or spleen cells. The adoptive anti-DNP response restored by unprimed or primed cells was not affected by [(3)H]thymidine treatment. This indicates that both populations of cells turn over slowly. However, our previous studies show that unprimed B cells involved in the adoptive antibody response to ferritin turn over rapidly. The different findings are discussed in the context of antigen-dependent B-cell maturation.

    View details for DOI 10.1084/jem.138.6.1331

    View details for Web of Science ID A1973R570500004

    View details for PubMedID 4543454

    View details for PubMedCentralID PMC2139472

  • BIOLOGICAL CHARACTERISTICS OF T AND B MEMORY LYMPHOCYTES IN RAT JOURNAL OF EXPERIMENTAL MEDICINE STROBER, S., DILLEY, J. 1973; 137 (5): 1275–92

    Abstract

    The adoptive secondary antibody response of rats to the hapten-protein conjugate dinitrophenyl-diphtheria toxoid (DNP-DT) was used to investigate the migratory properties and rate of formation of T and B memory cells in the spleen. The experimental findings show that hapten (DNP-BSA)- and carrier (DT)-primed spleen cells act synergistically in the restoration of the adoptive anti-DNP response. Passage of both hapten- and carrier-primed spleen cells through an intermediate host (intravenous injection and subsequent collection in the thoracic duct lymph) showed that both cell types are able to recirculate from the blood to the lymph. In addition, memory to the hapten or carrier could be withdrawn from the spleen by prolonged thoracic duct drainage. The rate of formation of hapten- and carrier-primed spleen cells was studied by treating donors with [(3)H]thymidine for 48 h before cell transfer in an attempt to "suicide" rapidly dividing cells. Only a slight reduction in the adoptive response to the hapten or carrier was noted upon transfer of treated cells to irradiated hosts. In further experiments, the cell lineage of hapten- and carrier-primed cells was determined by treating each cell type in vitro with rabbit antirat B cell serum (RARBS) and complement. Although treatment with RARBS did not affect the adoptive response restored by carrier-primed cells, the same treatment abolished the response restored by hapten-primed cells. These findings indicate that T and B memory cells in the spleen of the rat are relatively long-lived, recirculating lymphocytes. The contribution of fixed or rapidly turning over cells to immunological memory is small or negligible as compared with the latter cells.

    View details for DOI 10.1084/jem.137.5.1275

    View details for Web of Science ID A1973P573400012

    View details for PubMedID 4540800

    View details for PubMedCentralID PMC2139239