T-cell mediated immune rejection is the major barrier to organ transplantation in humans. It is therefore surprising that donor specific blood transfusions, that might be expected to prime alloreactive T cells in the recipient, often lead to immunosuppression. A potential explanation for this paradox may be provided by recent studies on the activation requirements of T cells. These cells require two different sets of signals to be maximally activated. One set of signals is transduced through the T cell antigen receptor (TCR)/CD3 complex when these molecules interact with complexes of antigenic peptides bound to major histocompatibility complex (MHC)-encoded molecules on the surface of antigen-presenting cells (APC). The second set of signals are provided by APC-derived, non-specific costimulatory factors. If T cells receive TCR occupancy in the absence of costimulatory signals in vitro, they become unresponsive, or anergic, i.e., they are unable to respond to normally immunogenic stimuli. Therefore, it is conceivable that the """"""""transfusion effect"""""""" mentioned above is related to anergy induction in recipient T cells following alloantigen presentation by costimulation-deficient APC in the transfused inoculum. The broad objective of this proposal is to apply our understanding of the mechanism of anergy induction in vitro to the problem of T cell-mediated allograft rejection in vivo. Specifically, the biochemical and cellular requirements for inducing alloantigen-specific anergy will be characterized in murine T cell clones in vitro; the mechanism by which rapamycin facilitates anergy induction in alloantigen-specific T cell clones will be investigated; based on the information gained from the in vitro studies, allogeneic APC that are poor providers of costimulatory signals will be transfused alone or concomitantly with rapamycin treatment into miniature swine to determine if kidney allograft tolerance can be achieved; and if transplantation tolerance can be induced in miniature swine, the functional capacities of graft infiltrating lymphocytes from the tolerant animals will be studied in vitro to gain information on the tolerance mechanism. If successful in miniature swine, this protocol could easily be applied to humans with the hope of inducing donor-specific unresponsiveness without the risks associated with non-specific immunosuppressive drugs or irradiation.
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