The molecular and spatial interactions between antibody suppressor CD8+ T cells and B cells that regulate alloantibody production after transplant

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Project Summary/Abstract Donor specific antibodies (DSA) develop in transplant recipients despite immunosuppression and is a significant cause of acute and chronic graft loss across multiple organs. Antibody mediated rejection (AMR) treatment options are non-specific, have variable efficacy, and do not improve long-term outcomes. An effective treatment for AMR remains an unmet need, and a better understanding of mechanisms that regulate humoral immunity are critical to develop more effective therapies. We have discovered a novel subset of CD8+ T cells (CD8+ TAb- supp) that suppresses alloantibody production in part through the killing of alloprimed B cells. Notably, adoptive transfer of CD8+ TAb-supp cells into murine recipients after allogeneic cellular and solid organ transplant results in decreased alloantibody quantity, improved AMR-associated histopathology, and enhanced graft survival. Moreover, our lab has determined that a human CD8+ T cell subset with the same phenotype as murine CD8+ TAb-supp cells is detected in the peripheral circulation of human kidney transplant recipients and their quantity inversely correlates with the development of DSA. The objective of this proposal is to characterise the molecular mechanisms by which CD8+ TAb-supp cells 1) exert their antibody-suppressive effect upon alloprimed B cells and 2) traffic to and from lymphoid depots. The translational impact of this project is high and as a postdoctoral fellow and surgery resident I look forward to gaining rigorous training in immunology research and to preparing myself for a transplant surgeon-scientist career. I chose the Ohio State University (OSU) General Surgery Residency Program because of its breadth and volume of surgery, including one of the top ten transplant centers in the country, and the program’s commitment (and protected time) for research training. OSU is one of the largest public institutions, comprising fifteen colleges and a Graduate School that offers nearly 100 doctoral degree programs. My training plan includes completion of a doctoral degree through the Biomedical Sciences Graduate Program with a research emphasis in immunology that includes coursework in advanced immunology, research ethics, biostatistics, and grant writing. I will pursue research related seminars, workshops, and conferences offered by the OSU Center for Clinical Translational Science, Comprehensive Transplant Center, Pelotonia ImmunoOncology Institute, and Diabetes Research Center. I will gain research training and career advice from my Sponsor (Ginny L. Bumgardner MD PhD) and Co-Sponsor (Peter Stock MD PhD, University of California San Francisco), both of whom are transplant surgeon-scientists. I will broaden my understanding of immunology research through interactions with a diverse Career Advisory Committee consisting of Eugene Oltz PhD (Chair, Microbial Infection and Immunity), Robert Baiocchi MD PhD (Director, OSU Physician Scientist Training Program), and Willa Hsueh MD (Director, Diabetes Research Center). I will present results of my research to my Career Advisory Committee on a quarterly basis. I plan to disseminate my research findings through publications in peer-reviewed journals, presentations at OSU research forums, and attendance at national scientific meetings.