Tolerance for Xenogeneic Islet Cell Transplantation in Non-human Primates

Xenogeneic islet transplantation is an attractive therapeutic option for achieving insulin independence in diabetic patients, provided that anti-xenogeneic immune responses can be effectively inhibited without the need for aggressive and clinically incompatible immunosuppression. In the previous two JDRF-funded periods, we have successfully modified our effective tolerance regimen of alloantigen delivery via apoptotic ECDI-fixed donor cells to xenoantigen delivery for tolerance induction to porcine xenogeneic islets, initially in a pig-to-mouse islet transplant model and now in a pig-to-monkey islet transplant model. Based on knowledge gained during the previous funding periods, we propose to continue our studies with now a new focus on the requirement for the maintenance of durable and stable xenogeneic tolerance, and the critical role of B cells in maintaining tolerance stability. Our hypothesis is that B cells play a crucial but differential role in early vs. late xenogeneic islet rejection: during early rejection, B cells predominantly prime anti-xenogeneic IL-17 response and differentiate to anti-xenogeneic antibody producing plasma cells; in contrast, during late rejection, B cells predominantly prime anti-xenogeneic IFN- response without differentiating to anti-xenogeneic antibody producing plasma cells. Consequently, prevention of late B cell-mediated Th1 priming would effectively prevent late rejection of porcine islet xenografts and ensure maintenance of long-term xenogeneic tolerance. We propose to test our hypothesis in pig-to-mouse (Aim 1), pig-to-humanized mouse (Aim 2) and pig-to-monkey (Aim 3) xenogeneic islet transplantation models, with the ultimate goal of gaining critical knowledge for the eventual design of clinical tolerance protocol for pig-to-human xenogeneic islet transplantation.