Over the past few years, transplantation of different organs has become routine from a technical point of view. There remain, however, two major unresolved obstacles--graft rejection, and/or the side effects of immunosuppressive drugs, and an inadequate source of donated organs. The obstacle of a limited supply is so severe that many potential recipients succumb while awaiting a suitable donor. Although numerous avenues should be pursued in an effort to eliminate these shortages, the one that excites us most is the possibility of xenotransplantation. Because of availability, cattle or pigs may be the ultimate donor source. However, for xenotransplantation to have any possibility of succeeding initially, we believe it will require that donor animals be other primates. Even though cardiac allotransplantation is quite successful, many fundamental issues remain to be assessed before xenotransplantation can be viewed as practical. Because of the tremendous number of inbred strains of mice and rats with defined genetics, they have been exceedingly valuable in defining immune reactivities that underlie mechanisms of allograft rejection/acceptance. Based on this information, it is advantageous to continue to utilize this genetic material in studies on any of a number of fundamental aspects of xenograft rejection/acceptance. Specifically, the aims of this proposal are to: (a) characterize the cell-types involved in a cell-mediated mouse/rat model of xenograft rejection; (b) characterize antibodies that underlie both hyperacute and chronic rejection of xenografts; and (c) assess genetic controls that are manifested at the level of the recipient as well as the donor on rejection/acceptance of xenografts.
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