This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. To maintain allografts patients must adhere to life-long treatment regimens using costly immunosuppressive agents that dramatically increase the risks of cardiovascular disease, infections and malignancy. The development of strategies to promote the acceptance of allogenic tissues without the need for chronic immunosuppressant could reduce the risk of these complications and greatly expand the application of organ, tissue, and cellular transplantation for diseases such as the hemoglobinopathies and genetic immunodeficiencies, Type 1 diabetes and other autoimmune diseases. We continue to lead an effort to determine the degree of family relatedness and 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 know genetic and MHC disparity for the first time. Our data suggest that the setting of increased MHC matching between transplant donors and recipients, Costimulation blockade-based induction of durable Chimerism can be achieved. However, rejection still occurs, even with full MHC matching. We have continued experiments with Rhesus transplant pairs with a known degree of relatedness and MHV matching. Our results 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.
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