Chronic rejection of transplanted organs remains the primary cause of graft failure over time despite advances in immunosuppression. Memory T cells and production of antibodies by B cells are recognized as important mediators of chronic rejection but are not effectively controlled by current immunosuppression regimens. We find that antibody-independent functions of B cells also play a significant role in the pathogenesis of alloimmunity and chronic rejection by presenting antigen and providing costimulation to T cells. Here, we will test the hypothesis that B cell interactions with T cells play a key role in the development, maintenance and recall of T cell memory. We propose to (a) delineate when, where and which B cells interact with T cells in shaping memory responses, and (b) test whether blocking these interactions will prevent chronic rejection. Non-selective targeting of B cells by global depletion strategies may be detrimental as it also removes B cells with regulatory functions. Understanding which specific B cell populations interact with T cells, when and where they function to sustain long-lived memory is therefore a clinically relevant and significant goal. Results from these proposed studies would allow us to develop novel therapies that inhibit T cell memory and prevent chronic rejection by targeting specific functions, subpopulations and/or migration of B cells.

Public Health Relevance

Chronic allograft rejection remains the leading cause of failure of a transplanted organ, and is mediated by B cells and memory T cells. We will investigate when, where, and which B cells interact with T cells in shaping long-lived (memory) immune responses that cause rejection. Understanding these mechanisms will assist in the development of novel therapies that will target specific functions of B cells to inhibit memory T cells and prevent chronic rejection to improve long-term survival of transplanted organs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI079177-06
Application #
9382844
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Rice, Jeffrey S
Project Start
2008-09-23
Project End
2021-10-31
Budget Start
2017-11-01
Budget End
2018-10-31
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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