Despite advances in immunosuppression, long-term allograft survival remains sub-optimal due to unabated chronic rejection that causes relentless graft attrition. B cells and memory T cells contribute to chronic rejection of transplanted organs. Current immunosuppressive regimens inhibit neither B cells nor memory T cells effectively, and hence, fail to control chronic rejection. Therefore, investigating how B cells and T cells interact to promote long-lived immune responses that cause chronic allograft rejection is essential for developing novel therapies. Our preliminary data indicate that B cells provide important signals for alloreactive T cells to differentiate into long-lived memory lymphocytes. We hypothesize that B cells are a crucial link between the innate and adaptive immune response to a transplanted organ and promote generation of memory T cells that cause allograft rejection. The goal of this grant application is to investigate which B cell subsets are critical and how they are activated to provide help for T cell differentiation in the context of transplantation.
The specific aims are: (a) to investigate which B cell subsets promote T cell differentiation to memory in alloimmunity;(b) to investigate how B cells are activated to promote T cell differentiation to memory in alloimmunity;and (c) to investigate if B cell depletion inhibits T cell differentiation to memory and prevents chronic allograft rejection.
The specific aims will be accomplished using mixed bone marrow chimeras and transgenic mice to test the roles of B cell subsets, B cell innate activation and B cell depletion on development of T cell memory and chronic allograft rejection. The results of the proposed experiments will provide rationale for how and when to target B cells to prevent chronic allograft rejection and improve long-term survival of organ transplants.

Public Health Relevance

B cells and memory T cells cause acute and chronic allograft rejection that leads to loss of transplanted organs. We will investigate how B cells interact with T cells to generate long-lived (memory) immune responses that cause allograft rejection. Understanding these mechanisms will assist in the development of novel therapies that will target B cells and memory T cells to improve long-term survival of transplanted organs.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Transplantation, Tolerance, and Tumor Immunology (TTT)
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Kehn, Patricia J
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
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Hoffman, William; Lakkis, Fadi G; Chalasani, Geetha (2016) B Cells, Antibodies, and More. Clin J Am Soc Nephrol 11:137-54
Zeng, Qiang; Ng, Yue-Harn; Singh, Tripti et al. (2014) B cells mediate chronic allograft rejection independently of antibody production. J Clin Invest 124:1052-6
Zecher, Daniel; Li, Qi; Williams, Amanda L et al. (2012) Innate immunity alone is not sufficient for chronic rejection but predisposes healed allografts to T cell-mediated pathology. Transpl Immunol 26:113-8
Ng, Y-H; Oberbarnscheidt, M H; Chandramoorthy, H C K et al. (2010) B cells help alloreactive T cells differentiate into memory T cells. Am J Transplant 10:1970-80