The ultimate goal of the studies in this Program Project is the restoration of thymic function in AIDS patients by replacement of HIV-infected thymic stroma with healthy porcine tissue through thymic xenotransplantation. Previous studies in a murine model demonstrated the capacity of porcine fetal thymus transplants to reconstitute normal T cell populations in thymectomized, T cell-depleted animals. The current project is directed toward extending these findings to non-human primates as a preclinical model. As donors, we are utilizing 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. In the previous funding period, we have established conditions for successful engraftment of juvenile pig thymus into peripheral sites in autologous and allogeneic miniature swine. We have found the combination of omentum plus either muscle or renal capsule to be most effective sites for implantation of thymic tissue in these large animals. We have also initiated studies of porcine thymic transplantation into baboons. Our preliminary data demonstrate successful engraftment of pig thymic tissue in thymectomized, T cell-depleted baboons for up to 60 days by histologic criteria. We have demonstrated recovery of CD4SP/CD45RA high cells in thymic grafted animals, but not in controls not receiving thymus, and specific depression of the baboon anti-pig MLR for several months after transplantation. We have also demonstrated the feasibility of transplanting vascularized pig thymus as part of a composite organ.
Our specific aims for the current proposal are to: 1) Achieve successful long-term engraftment of porcine thymus transplants in non-human primates; 2) Evaluate immune reconstitution of thymectomized, T cell depleted recipients following porcine thymic transplantation; and 3) Combine thymic transplantation with peripheral stem cell transplantation for induction of tolerance. The results of these studies could have important implications for the application of this treatment modality to patients suffering from AIDS.
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