Allograft rejection remains a major problem in clinical transplantation. In the first year post transplantation, nearly 20% of first cadaver renal allografts and 35% of retransplant grafts are rejected irreversibly despite the use of cyclosporine. Moreover, approximately 50% of renal allograft recipients suffer an acute rejection episode in the early post transplantation period which threatens the long term function of the graft and mandates additional immunosuppressive therapy. Finally, even patients who are successfully engrafted at one year are likely to subsequently reject their renal or cardiac allografts within the first decade following transplantation. By the far the best hope for improving graft survival, and particularly for preventing chronic rejection, is the induction of a state of """"""""tolerance"""""""" to the graft in the host. This project will investigate strategies for achieving tolerance in an established subhuman primate model of renal transplantation. These strategies will employ the administration of alloantigen in the form of synthetic peptides representing the polymorphic regions of MHC molecules. The selection of these peptides and their route of administration will be designed to be tolerogenic rather than immunogenic. This alloantigen administration will in some cases be accompanied by highly specific manipulations of the host immune response utilizing monoclonal antibodies and antibody-toxin conjugates directed at restricted lymphocyte subsets. These manipulations will be facilitated by the availability of bifunctional antibodies which can target two antigens on the target cell surface. The overall aim will be to develop a pre-clinical model of graft acceptance without the need for long term immunosuppression that can be brought to human trial. The highly conserved nature of the amino acid sequence of the major histocompatibility complex between man and subman primates makes the model to be employed uniquely valuable for this endeavor. To achieve this overall goal, this project will: 1) investigate the ability of allopeptide administration to prolong allograft survival in a murine model of heterotopic cardiac transplantation as a precursor to the primate studies; 2) select appropriate allopeptides derived from the MHC of the rhesus monkey and characterize the effect of both in vitro and in vivo administration of these peptides on the immune response: 3) determine whether the immune response of the rhesus monkey can be manipulated by administration of highly specific bifunctional monoclonal antibodies and antibody toxin conjugates; and 4) use the information derived to develop a protocol for long term graft survival in the rhesus monkey employing allopeptide administration with or without adjunctive immunosuppression. Throughout the project emphasis will be placed on the oral administration of allopeptides as a route to tolerance. The project will benefit directly from the experience with the allopeptides and the development of bifunctional antibody-toxin conjugates in the other projects of this program project. The protocols developed will be of direct relevance to clinical transplantation.
