Although titration of immunosuppressive drugs is generally manageable of allotransplantation, it poses a much greater problem in the case of xenografts, for which the amount of suppression required to avoid rejection has led to unacceptable susceptibility to infection. The goal of this proposal is the induction of transplantation tolerance to discordant xenografts in non-human primates, which would reduce or eliminate the need for non-specific immunosuppressive drugs. Our preliminary data suggest the feasibility of applying a mixed chimerism approach to this problem, an approach already used successfully in this laboratory for allografts and concordant xenografts in rodents and in cynomolgus monkeys. We have preliminary and encouraging data showed modifications of xenogeneic immune responses following bone marrow engraftment in pig bone marrow engraftment in baboons by th4e use of high dose pig peripheral blood stem cells and pig recombinant cytokines; 2) Testing in baboons the effect of porcine thymus transplantation, which has previously been successful in inducing xenograft tolerance in rodents; and 3) Applying the findings of Aim 1 and 2, as well as strategies developed in the other projects of the Program Project, to the mixed chimerism approach as a means of inducing transplantation tolerance to organ xenografts in the discordant pig to baboon combination. This project thus represents the preclinical testing of strategies developed throughout the Program Project. In addition, the experiments planned will provide basic information on xenogeneic stem cell engraftment and on the immunologic pathways responsible for xenogeneic rejection and tolerance induction in primates. As such, these studies should have both theoretical and practical implications for the eventual application of xenotransplantation as a clinical modality.
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