The thymus, which plays a central role in T cell development, is a major target of HIV infection. Following its destruction, like likelihood is small that immune reconstitution could be achieved even if viral replication could be adequately suppressed. In addition, infected thymic stroma may provide a source of HIV infection to new T cells which develop in the thymus. Recent studies in a murine model have demonstrated the capacity of porcine fetal thymus transplants to reconstitute normal T cell populations in thymectomized, T cell-depleted animals. The overall goal of this proposal is to extend these findings to a preclinical primate model by determining the conditions required to achieve engraftment of, and host T cell reconstitution y, pig thymic transplants in rhesus monkeys. As donors, we will utilize partially inbred miniature swine which have been developed in this laboratory as a large animal model in which MHC genetics can be reproducibly controlled, and which are of appropriate size and availability to serve as xenograft donors for eventual clinical use. Specifically, we will: 1) Determine the conditions for successful grafting of fetal and/or neonatal pig thymus tissue in rhesus monkeys; 2) Evaluate the immunocompetence of rhesus monkey T cells that develop in pig thymic grafts in monkeys; and 3) Determine the capacity of porcine hematopoietic cells to reconstitute the lymphohematopoietic system of rhesus monkeys engrafted with swine thymic tissue. We will begin with a nonmyeloblative conditioning regimen which we have recently demonstrated to be capable of permitting engraftment of swine bone marrow progenitor cells in cynomolgus monkeys for more than six months. After conditions for thymic engraftment are determined in normal monkeys, requirements for components of the conditioning regimen in rhesus monkeys at different stages of SIV infection will be assessed in Project 3 of this Program Project. The results of these studies could have important implications for the application of this treatment modality to patients at different stages of AIDS disease.
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