While transplantation represents life-saving therapy for many patients with end-stage organ failure, longtermoutcomes of transplant remain inadequate, with high rates of chronic organ rejection and theequirement for life-long therapy with costly immunosuppressive agents that dramatically increase the risksof cardiovascular disease, infections and malignancies. The development of strategies to promote theacceptance of allogeneic tissues without the need for chromic immunosupression could not only reduce therisk of these life-threatening complications, but also greatly expand the application of organ, tissue andcellular transplantation. In rodent models, strategies using CD28 and CD40/154 T cell costimulationblockade in the setting of mixed-chimerism induction have led to robust tolerance to both bone marrow andsolid organ allografts. In this proposal, we will test this combined costimulation blockade/chimerisminductionstrategy in Rhesus macaques in order to rigorously determine the requirements to translate theresults in rodent models to clinical care. The unifying purpose of our proposal is to develop clinicallyapplicable protocols for the induction of tolerance to solid organ allografts while preserving immunecompetence in the transplant recipient. In order to accomplish this goal, a detailed understanding of thedegree 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 arerequired. This core will be focused on providing these key cross-project evaluations that will be crucial tothe success of both of the projects described in this proposal.
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