Cameron Scott Bader

All Publications

• Mobilized Mouse and Human Peripheral Blood Containing Elevated Numbers of Donor Treg Cells Ameliorates Pre-Clinical GvHD and GVL Is Maintained in an MHC-Matched Allogeneic Murine Model Barreras, H., Copsel, S. N., Ding, Y., Cash, C. J., Bader, C. S., Benjamin, C. L., Komanduri, K. V., Malek, T. R., Levy, R. B. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-153092

  View details for Web of Science ID 000736413903065

• Use of Post-transplant Cyclophosphamide Treatment to Build a Tolerance Platform to Prevent Liquid and Solid Organ Allograft Rejection. Frontiers in immunology Lightbourn, C. O., Wolf, D., Copsel, S. N., Wang, Y., Pfeiffer, B. J., Barreras, H., Bader, C. S., Komanduri, K. V., Perez, V. L., Levy, R. B. 2021; 12: 636789

  Abstract

  Corneal transplantation (CT) is the most frequent type of solid organ transplant (SOT) performed worldwide. Unfortunately, immunological rejection is the primary cause of graft failure for CT and therefore advances in immune regulation to induce tolerance remains an unmet medical need. Recently, our work and others in pre-clinical studies found that cyclophosphamide (Cy) administered after ("post-transplant," PTCy) hematopoietic stem cell transplantation (HSCT), i.e., liquid transplants is effective for graft vs. host disease prophylaxis and enhances overall survival. Importantly, within the past 10 years, PTCy has been widely adopted for clinical HSCT and the results at many centers have been extremely encouraging. The present studies found that Cy can be effectively employed to prolong the survival of SOT, specifically mouse corneal allografts. The results demonstrated that the timing of PTCy administration is critical for these CT and distinct from the kinetics employed following allogeneic HSCT. PTCy was observed to interfere with neovascularization, a process critically associated with immune rejection of corneal tissue that ensues following the loss of ocular "immune privilege." PTCy has the potential to delete or directly suppress allo-reactive T cells and treatment here was shown to diminish T cell rejection responses. These PTCy doses were observed to spare significant levels of CD4+ FoxP3+ (Tregs) which were found to be functional and could readily receive stimulating signals leading to their in vivo expansion via TNFRSF25 and CD25 agonists. In total, we posit future studies can take advantage of Cy based platforms to generate combinatorial strategies for long-term tolerance induction.

  View details for DOI 10.3389/fimmu.2021.636789

  View details for PubMedID 33737937

  View details for PubMedCentralID PMC7962410

• STING and transplantation: can targeting this pathway improve outcomes? Blood Bader, C. S., Jin, L., Levy, R. B. 2021; 137 (14): 1871-1878

  Abstract

  Stimulator of interferon genes (STING) is an innate immune sensor of cytoplasmic dsDNA originating from microorganisms and host cells. STING plays an important role in the regulation of murine graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and may be similarly activated during other transplantation modalities. In this review, we discuss STING in allo-HSCT and its prospective involvement in autologous HSCT (auto-HSCT) and solid organ transplantation (SOT), highlighting its unique role in nonhematopoietic, hematopoietic, and malignant cell types.

  View details for DOI 10.1182/blood.2020008911

  View details for PubMedID 33619537

  View details for PubMedCentralID PMC8033456

• TNFRSF25 and CD25 Stimulation Expands Tregs and ILC2s in the GI Tract: Recipient Modulation Pre-HSCT Lightbourn, C. O., Copsel, S. N., Bader, C. S., Wolf, D., Banrreras, H., Levy, R. B. ELSEVIER SCIENCE INC. 2020: S54

  View details for Web of Science ID 000516887900073

• The Innate Immune Sensor Sting Promotes Donor CD8(+) T Cell Activation and Recipient APC Death Early after Preclinical Allogeneic Hematopoietic Stem Cell Transplantation Bader, C. S., Barreras, H., Lightbourn, C. O., Copsel, S. N., Wolf, D., Meng, J., Ahn, J., Komanduri, K. V., Blazar, B. R., Jin, L., Barber, G. N., Roy, S., Levy, R. B. ELSEVIER SCIENCE INC. 2020: S29

  View details for Web of Science ID 000516887900036

• IL-2/IL-2R, TL1A/TNFRSF25 or Their Combined Stimulation Results in Distinct CD4+FoxP3+Regulatory T Cell Phenotype and Suppressive Function Copsel, S. N., Barreras, H., Lightbourn, C. O., Bader, C. S., Wolf, D., Kale, B., Alperstein, W., Komanduri, K. V., Levy, R. B. ELSEVIER SCIENCE INC. 2020: S169

  View details for Web of Science ID 000516887900244

• STING differentially regulates experimental GVHD mediated by CD8 versus CD4 T cell subsets. Science translational medicine Bader, C. S., Barreras, H., Lightbourn, C. O., Copsel, S. N., Wolf, D., Meng, J., Ahn, J., Komanduri, K. V., Blazar, B. R., Jin, L., Barber, G. N., Roy, S., Levy, R. B. 2020; 12 (552)

  Abstract

  The stimulator of interferon genes (STING) pathway has been proposed as a key regulator of gastrointestinal homeostasis and inflammatory responses. Although STING reportedly protects against gut barrier damage and graft-versus-host disease (GVHD) after major histocompatibility complex (MHC)-mismatched allogeneic hematopoietic stem cell transplantation (aHSCT), its effect in clinically relevant MHC-matched aHSCT is unknown. Studies here demonstrate that STING signaling in nonhematopoietic cells promoted MHC-matched aHSCT-induced GVHD and that STING agonists increased type I interferon and MHC I expression in nonhematopoietic mouse intestinal organoid cultures. Moreover, mice expressing a human STING allele containing three single-nucleotide polymorphisms associated with decreased STING activity also developed reduced MHC-matched GVHD, demonstrating STING's potential clinical importance. STING-/- recipients experienced reduced GVHD with transplant of purified donor CD8+ T cells in both MHC-matched and MHC-mismatched models, reconciling the seemingly disparate results. Further examination revealed that STING deficiency reduced the activation of donor CD8+ T cells early after transplant and promoted recipient MHC class II+ antigen-presenting cell (APC) survival. Therefore, APC persistence in STING pathway absence may account for the increased GVHD mediated by CD4+ T cells in completely mismatched recipients. In total, our findings have important implications for regulating clinical GVHD by targeting STING early after aHSCT and demonstrate that an innate immune pathway has opposing effects on the outcome of aHSCT, depending on the donor/recipient MHC disparity.

  View details for DOI 10.1126/scitranslmed.aay5006

  View details for PubMedID 32669421

  View details for PubMedCentralID PMC7392054

• The Location of CD4(+)FoxP3(+) Cells with Regard to CD25 and TNFRSF25 Receptor Signals Matters: Different Requirements for GI and Peripheral Tregs Lightbourn, C. O., Lozano, C., Bader, C. S., Copsel, S. N., Wolf, D., Barreras, H., Levy, R. B. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-131076

  View details for Web of Science ID 000577160403192

• Multiple Pathways Targeting CD25 or TNFRSF25 Affect CD4(+)FoxP3(+) Regulatory T Cell Phenotype and Suppressive Function Copsel, S. N., Barreras, H., Lightbourn, C. O., Bader, C. S., Wolf, D., Kale, B., Alperstein, W., Komanduri, K. V., Levy, R. B. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-130649

  View details for Web of Science ID 000577164603162

• The Innate Immune Sensor Sting Promotes Donor CD8(+) T Cell Activation and Recipient APC Death Early after Preclinical Allogeneic Hematopoietic Stem Cell Transplantation Bader, C. S., Barreras, H., Lightbourn, C. O., Copsel, S. N., Wolf, D., Meng, J., Ahn, J., Komanduri, K. V., Blazar, B. R., Jin, L., Barber, G. N., Roy, S., Levy, R. B. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-130197

  View details for Web of Science ID 000577160408026

• The Innate Immune Sensor Sting Promotes CD8(+) T Cell-Mediated Gvhd after Preclinical Allogeneic Hematopoietic Stem Cell Transplantation Bader, C. S., Barreras, H., Lightbourn, C. O., Copsel, S., Meng, J., Ahn, J., Barber, G. N., Jin, L., Roy, S., Levy, R. B. ELSEVIER SCIENCE INC. 2019

  View details for Web of Science ID 000540655500064

• Development of a Concomitant Treg Expansion and Stem Cell Mobilization Protocol Which Enables Peripheral Blood Transplant Amelioration of Gvhd Following Pre-Clinical aHSCT Barreras, H., Bader, C. S., Copsel, S., Kale, B., Pfeiffer, B. J., Lozano, C., Lightbourn, C. O., Jurecic, R., Levy, R. B. ELSEVIER SCIENCE INC. 2019

  View details for Web of Science ID 000540655500436

• Identification of a BET Bromodomain Inhibitor That Enables Treg Function: A Combinatorial Strategy to Inhibit GVHD Copsel, S., Lightbourn, C. O., Barreras, H., Lohse, I., Wolf, D., Bader, C. S., Manov, J., Kale, B., Shah, D., Brothers, S., Perez, V. L., Komanduri, K. V., Wahlestedt, C., Levy, R. B. ELSEVIER SCIENCE INC. 2019

  View details for Web of Science ID 000540655500032

• Sequential Cyclophosphamide and Trametinib Improve Clinical Graft Versus Host Disease and Survival in Murine Hematopoietic Stem Cell Transplant Nahas, G., Barreras, H., Bader, C. S., Copsel, S., Wolf, D., Kale, B., Levy, R. B., Komanduri, K. V. ELSEVIER SCIENCE INC. 2019

  View details for Web of Science ID 000540655500443

• The Innate Immune Sensor Sting Regulates Intestinal Inflammation and GVHD after Allogeneic Hematopoietic Stem Cell Transplantation in Knock-out and Human Allele Knock-in Recipient Mice Bader, C. S., Barreras, H., Lightbourn, C. O., Copsel, S., Ahn, J., Barber, G. N., Jin, L., Levy, R. B. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-109999

  View details for Web of Science ID 000454837600119

• Use of Post-Transplant Cyclophosphamide Therapy in High Risk Corneal Graft Transplantation: A New Strategy to Prolong Corneal Allograft Survival Levy, R., Lightbourn, C., Wang, Y., Bader, C., Copsel, S., Pfeiffer, B., Perez, V. L. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2018

  View details for Web of Science ID 000442932800189

• Extremely Low Numbers of Donor Expanded Regulatory T Cells Characterized by Expression of an Activated Phenotype Can Suppress Graft-Versus-Host Disease Copsel, S., Wolf, D., Kale, B., Barreras, H., Lightbourn, C. O., Bader, C. S., Alperstein, W., Komanduri, K. V., Levy, R. B. ELSEVIER SCIENCE INC. 2018: S170

  View details for Web of Science ID 000425476000225

• The Innate Immune Sensor Sting Can Augment or Ameliorate Graft-Versus-Host Disease Dependent on the Genetic Disparity between Donors and Recipients Bader, C. S., Barreras, H., Lightbourn, C. O., Copsel, S., Ahn, J., Barber, G. N., Levy, R. B. ELSEVIER SCIENCE INC. 2018: S176-S177

  View details for Web of Science ID 000425476000234

• Very Low Numbers of CD4+ FoxP3+ Tregs Expanded in Donors via TL1A-Ig and Low-Dose IL-2 Exhibit a Distinct Activation/Functional Profile and Suppress GVHD in a Preclinical Model. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Copsel, S., Wolf, D., Kale, B., Barreras, H., Lightbourn, C. O., Bader, C. S., Alperstein, W., Altman, N. H., Komanduri, K. V., Levy, R. B. 2018; 24 (9): 1788-1794

  Abstract

  Regulatory T cells (Tregs) are essential for the maintenance of tolerance and immune homeostasis. In allogeneic hematopoietic stem cell transplantation (aHSCT), transfer of appropriate Treg numbers is a promising therapy for the prevention of graft-versus-host disease (GVHD). We have recently reported a novel approach that induces the marked expansion and selective activation of Tregs in vivo by targeting tumor necrosis factor receptor superfamily 25 (TNFRSF25) and CD25. A potential advance to promote clinical application of Tregs to ameliorate GVHD and other disorders would be the generation of more potent Treg populations. Here we wanted to determine if very low doses of Tregs generated using the "2-pathway" stimulation protocol via TL1A-Ig fusion protein and low-dose IL-2 (targeting TNFRSF25 and CD25, respectively) could be used to regulate preclinical GVHD. Analysis of such 2-pathway expanded Tregs identified higher levels of activation and functional molecules (CD103, ICOS-1, Nrp-1, CD39, CD73, il-10, and tgfb1) versus unexpanded Tregs. Additionally, in vitro assessment of 2-pathway stimulated Tregs indicated enhanced suppressor activity. Notably, transplant of extremely low numbers of these Tregs (1:6 expanded Tregs/conventional T cells) suppressed GVHD after an MHC-mismatched aHSCT. Overall, these results demonstrate that 2-pathway stimulated CD4+ FoxP3+ Tregs were quantitatively and qualitatively more functionally effective than unexpanded Tregs. In total, the findings in this study support the notion that such 2-pathway stimulated Tregs may be useful for prevention of GVHD and ultimately promote more widespread application of aHSCT in the clinic.

  View details for DOI 10.1016/j.bbmt.2018.04.026

  View details for PubMedID 29751114

  View details for PubMedCentralID PMC6163068

• BET Bromodomain Inhibitors Which Permit Treg Function Enable a Combinatorial Strategy to Suppress GVHD in Pre-clinical Allogeneic HSCT. Frontiers in immunology Copsel, S. N., Lightbourn, C. O., Barreras, H., Lohse, I., Wolf, D., Bader, C. S., Manov, J., Kale, B. J., Shah, D., Brothers, S. P., Perez, V. L., Komanduri, K. V., Wahlestedt, C., Levy, R. B. 2018; 9: 3104

  Abstract

  A recent approach for limiting production of pro-inflammatory cytokines has been to target bromodomain and extra-terminal (BET) proteins. These epigenetic readers of histone acetylation regulate transcription of genes involved in inflammation, cardiovascular disease, and cancer. Development of BET inhibitors (BETi) has generated enormous interest for their therapeutic potential. Because inflammatory signals and donor T cells promote graft-versus-host disease (GVHD), regulating both pathways could be effective to abrogate this disorder. The objective of the present study was to identify a BETi which did not interfere in vivo with CD4+FoxP3+ regulatory T cell (Treg) expansion and function to utilize together with Tregs following allogeneic hematopoietic stem cell transplantation (aHSCT) to ameliorate GVHD. We have reported that Tregs can be markedly expanded and selectively activated with increased functional capacity by targeting TNFRSF25 and CD25 with TL1A-Ig and low dose IL-2, respectively. Here, mice were treated over 7 days (TL1A-Ig + IL-2) together with BETi. We found that the BETi EP11313 did not decrease frequency/numbers or phenotype of expanded Tregs as well as effector molecules, such as IL-10 and TGF-β. However, BETi JQ1 interfered with Treg expansion and altered subset distribution and phenotype. Notably, in Treg expanded mice, EP11313 diminished tnfa and ifng but not il-2 RNA levels. Remarkably, Treg pSTAT5 expression was not affected by EP11313 supporting the notion that Treg IL-2 signaling remained intact. MHC-mismatched aHSCT (B6 → BALB/c) was performed using in vivo expanded donor Tregs with or without EP11313 short-term treatment in the recipient. Early post-transplant, improvement in the splenic and LN CD4/CD8 ratio along with fewer effector cells and high Treg levels in aHSCT recipients treated with expanded Tregs + EP11313 was detected. Interestingly, this group exhibited a significant diminution of GVHD clinical score with less skin and ocular involvement. Finally, using low numbers of highly purified expanded Tregs, improved clinical GVHD scores were observed in EP11313 treated recipients. In total, we conclude that use of this novel combinatorial strategy can suppress pre-clinical GVHD and posit, in vivo EP11313 treatment might be useful combined with Treg expansion therapy for treatment of diseases involving inflammatory responses.

  View details for DOI 10.3389/fimmu.2018.03104

  View details for PubMedID 30733722

  View details for PubMedCentralID PMC6353853

• Superior immune reconstitution using Treg-expanded donor cells versus PTCy treatment in preclinical HSCT models. JCI insight Wolf, D., Bader, C. S., Barreras, H., Copsel, S., Pfeiffer, B. J., Lightbourn, C. O., Altman, N. H., Komanduri, K. V., Levy, R. B. 2018; 3 (20)

  Abstract

  Posttransplant cyclophosphamide (PTCy) has been found to be effective in ameliorating acute graft-versus-host disease (GVHD) in patients following allogeneic hematopoietic stem cell transplantation (aHSCT). Adoptive transfer of high numbers of donor Tregs in experimental aHSCT has shown promise as a therapeutic modality for GVHD regulation. We recently described a strategy for in vivo Treg expansion targeting two receptors: TNFRSF25 and CD25. To date, there have been no direct comparisons between the use of PTCy and Tregs regarding outcome and immune reconstitution within identical groups of transplanted mice. Here, we assessed these two strategies and found both decreased clinical GVHD and improved survival long term. However, recipients transplanted with Treg-expanded donor cells (TrED) exhibited less weight loss early after HSCT. Additionally, TrED recipients demonstrated less thymic damage, significantly more recent thymic emigrants, and more rapid lymphoid engraftment. Three months after HSCT, PTCy-treated and TrED recipients showed tolerance to F1 skin allografts and comparable immune function. Overall, TrED was found superior to PTCy with regard to weight loss early after transplant and initial lymphoid engraftment. Based on these findings, we speculate that morbidity and mortality after transplant could be diminished following TrED transplant into aHSCT recipients, and, therefore, that TrED could provide a promising clinical strategy for GVHD prophylaxis.

  View details for DOI 10.1172/jci.insight.121717

  View details for PubMedID 30333311

  View details for PubMedCentralID PMC6237457

• Epigenetic Regulation Together with Treg Expansion: A New Combinatorial Strategy for Application in Experimental Allogeneic HSCT Copsel, S., Manov, J., Lightbourn, C. O., Barreras, H., Bader, C. S., Pfeiffer, B. J., Shah, D., Wolf, D., Komanduri, K. V., Wahlestedt, C., Levy, R. B. ELSEVIER SCIENCE INC. 2017: S313-S314

  View details for Web of Science ID 000540635000429

• Marked in Vivo Donor Regulatory T Cell Expansion via Interleukin-2 and TL1A-Ig Stimulation Ameliorates Graft-versus-Host Disease but Preserves Graft-versus-Leukemia in Recipients after Hematopoietic Stem Cell Transplantation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Wolf, D., Barreras, H., Bader, C. S., Copsel, S., Lightbourn, C. O., Pfeiffer, B. J., Altman, N. H., Podack, E. R., Komanduri, K. V., Levy, R. B. 2017; 23 (5): 757-766

  Abstract

  Regulatory T cells (Tregs) are critical for self-tolerance. Although adoptive transfer of expanded Tregs limits graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT), ex vivo generation of large numbers of functional Tregs remains difficult. Here, we demonstrate that in vivo targeting of the TNF superfamily receptor TNFRSF25 using the TL1A-Ig fusion protein, along with IL-2, resulted in transient but massive Treg expansion in donor mice, which peaked within days and was nontoxic. Tregs increased in multiple compartments, including blood, lymph nodes, spleen, and colon (GVHD target tissue). Tregs did not expand in bone marrow, a critical site for graft-versus-malignancy responses. Adoptive transfer of in vivo-expanded Tregs in the setting of MHC-mismatched or MHC-matched allogeneic HSCT significantly ameliorated GVHD. Critically, transplantation of Treg-expanded donor cells facilitated transplant tolerance without GVHD, with complete sparing of graft-versus-malignancy. This approach may prove valuable as a therapeutic strategy promoting transplantation tolerance.

  View details for DOI 10.1016/j.bbmt.2017.02.013

  View details for PubMedID 28219835

  View details for PubMedCentralID PMC5625339

• Marked In Vivo Expansion of Donor T Regulatory Cells Via Targeting of the IL-2/CD25 and TL1A/TNFRSF25 Pathways Elicits Gender Differences and Ameliorates Gvhd Wolff, D., Barreras, H., Bader, C. S., Razdan, S., Lightbourn, C. O., Pfeiffer, B. J., Elliot, S., Podack, E. R., Komanduri, K. V., Levy, R. B. ELSEVIER SCIENCE INC. 2016: S418

  View details for DOI 10.1016/j.bbmt.2015.11.956

  View details for Web of Science ID 000370910300631

• Targeting the IL-2/CD25 and TL1A/TNFRSF25 Pathways: A New Approach to Markedly Expand Donor Tregs in Multiple Compartments Leads to in Situ Immune Regulation Wolf, D., Barreras, H., Bader, C. S., Lightbourn, C. O., Pfeiffer, B. J., Podack, E. R., Komanduri, K. V., Levy, R. B. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368021801223