TRANSPLANT TOLERANCE IN NONHUMAN PRIMATES

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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. To maintain their allografts, patients must rigidly adhere to life-long treatment regimens using costly immunosuppressive agents that dramatically increase the risks of cardiovascular disease, infections and malignancies. The development of strategies to promote the acceptance of allogeneic tissues without the need for chromic immunosupression could not only reduce the risk of these life-threatening complications, but also greatly expand the application of organ, tissue and cellular transplantation for diseases such as the hemoglobinopathies and genetic immunodeficiencies, Type I diabetes, and possibly other autoimmune diseases. We continued to lead an effort to determine the degree of family relatedness and the degree of MHC matching in Rhesus macaques. This analysis has fundamentally changed the way hematopoietic stem cell transplants are performed and analyzed in the Rhesus model and have allowed transplants between donors and recipients of known genetic and MHC disparity for the first time. Our data suggests that in the setting of increased MHC matching between transplant donors and recipients, costimulation blockade-based induction of durable chimerism can be achievable, but that rejection still occurs, even with full MHC matching. We continued experiments with Rhesus macaque transplant pairs with known degree of relatedness and degree of MHC matching. Our experiments indicate that the addition of either CD40-directed or LFA-1 directed costimulation/adhesion blockade can significantly enhance donor chimerism induction and, that in some cases, it is durable. We are continuing our prospective monitoring of chimerism and immune tolerance in these transplant cohorts. In 2009 we performed renal allograft transplants from the bone marrow donors. To date, given this regimen, we found that we can have persistent myeloid chimerism with rejection of the renal allograft.