While transplantation represents life-saving therapy for many patients with end-stage organ failure, longterm outcomes of transplant remain inadequate, with high rates of chronic organ rejection and the equirement for life-long therapy with 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. In rodent models, strategies using CD28 and CD40/154 T cell costimulation blockade in the setting of mixed-chimerism induction have led to robust tolerance to both bone marrow and solid organ allografts. In this proposal, we will test this combined costimulation blockade/chimerisminduction strategy in Rhesus macaques in order to rigorously determine the requirements to translate the results in rodent models to clinical care. The unifying purpose of our proposal is to develop clinically applicable protocols for the induction of tolerance to solid organ allografts while preserving immune competence in the transplant recipient. In order to accomplish this goal, a detailed understanding of the degree of MHC disparity between transplant donors and recipients, the immune consequences of transplant, and the protocols that allow the efficient expansion and analysis of adoptive immunotherapeutics are required. This core will be focused on providing these key cross-project evaluations that will be crucial to the success of both of the projects described in this proposal.
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