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)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56AI079177-05
Application #
8878494
Study Section
Transplantation, Tolerance, and Tumor Immunology Study Section (TTT)
Program Officer
Rice, Jeffrey S
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213