COSTIMULATION, CHIMERISM AND TOLERANCE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Transplantation is the preferred treatment for many forms of end-stage organ failure. While short-term results have improved, long-term outcomes remain inadequate. To maintain transplants, patients must rigidly adhere to life-long treatment regimens using costly immunosuppressive agents that dramatically increase risks of cardiovascular disease, infections and malignancies. Strategies to promote the acceptance of allogeneic tissues without chronic immunosupression could not only reduce the risk of life-threatening complications, but also greatly expand the application of transplantation. We have developed novel non-myelosuppressive protocols using anti-CD40L and CTLA4-Ig to permit the induction of titratable levels hematopoietic chimerism and robust deletional donor-specific tolerance in rodents. We aim to develop and optimize protocols to induce stable macrochimerism and transplantation tolerance to renal allografts in non-human primates. Even though engraftment of donor cells has been evident at very early time points, donor cells failed to persist beyond 100 days post transplant. We have explored the possibility that failure to develop persistent donor chimerism is due to previous transplant pairs not possessing any degree of family relationship or MHC matching, which are required prior to choosing transplant pairings clinically. A significant barrier existed to adhering to these same selection criteria for non-human primates, in that until recently, the NIH Primate colony at Yemassee, SC, did not collect data on either the degree of relatedness or of MHC disparity between potential transplant donors and recipients. We have undertaken the considerable responsibility of determining both parentage relationships between the animals in the colony and their degree of MHC similarity/disparity. We have thus far typed 142 animals and determined both their familial relationships and degree of MHC disparity. Thus, we can choose our transplant pairs to allow our planned 10 transplants in the coming year to test our costimulation-blockade paradigm for tolerance induction in the setting of known MHC disparity.