This proposal outlines studies designed to accomplish xenogeneic organ transplantation after establishing specific tolerance to these donors. Recently, an experimental system has been developed in which lethally irradiated mice have been reconstituted with syngeneic T-cell depleted bone marrow plus a larger inoculum of xenogeneic bone marrow. Evidence has been presented showing that these """"""""mixed"""""""" xenogeneic chimeras are generally immunocompetent but specifically hyporesponsive to the xenogeneic donor. This tolerance is not complete, however, and preliminary studies suggest that humoral mechanisms are responsible for chronic xenogeneic rejection in this system. The studies outlined here will develop further this transplantation model: first, to characterize the humoral mechanisms of rejection; second, to manipulate these humoral responses to accomplish more complete tolerance; and third, to modify the system to avoid the need for whole body irradiation in order to allow clinical application of these promising experiments. These studies will add to our understanding of the important biological and clinical problem of xenografting. They will also create a system for studying humoral rejection in both presensitized patients and those suffering chronic allograft rejection. Finally, they represent another effort to develop a clinically applicable method of accomplishing specific tolerance for organ transplantation.
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