Core B will provide key facilities and expertise for the mechanistic studies in Projects 1 and 2. Understanding the mechanisms underlying rejection and tolerance of heart and lung transplants in the primate experiments described in Projects 1 and 2 will not only help us achieve tolerance but will help us recognize when it is present or absent. The following methodologies will be utilized: 1. Determine the role of MHC disparities on alloresponses by MHC genotyping of donor and recipient monkeys; 2. Investigate the contributions of direct and indirect T cell alloresponses and autoimmune responses to acute/chronic graft rejection; 3. Monitor the frequency, phenotype, antigen specificity, and functions of donor-specific memory T cells present in blood and lymphoid organs of monkeys tested pre- and post-transplantation; 4. Monitor the frequency, phenotype, antigen specificity, and mechanisms of action of regulatory T cells and expand these cells in vitro for adoptive transfers experiments; 5. Analyze B cell subsets and antibodies as well as their functional properties; 6. Monitor pro- and anti-inflammatory cytokines in sera. The knowledge acquired from these experiments will be used to optimize mixed chimerism protocols designed to achieve tolerance of heart and lungs allografts and to assist in the successful translation of those tolerance protocols to the clinic.
The goal of Core B is to characterize the cells, soluble factors, and immune mechanisms implicated in the induction and maintenance of tolerance (indefinite survival of transplants without immunosuppression) to heart and lung transplants. Understanding the mechanisms by which tolerance is induced and maintained will contribute to the successful application of tolerance protocols to human heart and lung transplant recipients.
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