The majority of patients awaiting kidney transplantation have high frequency antibodies making it very difficult to match them with lymphocytotoxic crossmatch negative organs. In this setting a dilemma exists in that should highly sensitized patients with a positive crossmatch using stored, remote sera but a negative current crossmatch be transplanted; for in the absence of preformed antibody, will available immunosuppressive agents be able to prevent an anamnestic immune response and accelerated rejection. Because of this fear, most centers do not transplant in this situation. However, it is not really known whether newer and more potent immunosuppressants such as cyclosporin (CSA) may be able to suppress immune memory activation. The major aim of this project is to thoroughly evaluate the efficacy of CSA in the face of humoral presensitization. A rat model of hyperacute rejection will be used in which Lewis rats, presensitized to the ACI strain will be recipients of vascularized heterotopic ACI heart allografts. Such presensitized rats will be transplanted either at the time of peak antibody concentration or after it has decreased to a negligible level - situations analogous to the clinical crossmatch delemma described above. A correlative experiment will be performed utilizing naive Lewis rats adoptively transferred with lymphoid cells from highly sensitized syngeneic donors. CSA administered as a maintenance agent will be evaluated for its ability to prevent accelerated rejection in both of these """"""""crossmatch negative,"""""""" sensitized groups. Other agents will also be evaluated in this model including antithymocyte serum, cyclophosphamide and anti-B-cell monoclonal antibody. A second goal will be to see if treating newly sensitized rats with any of these agents will hasten the development of a negative crossmatch by stopping the ongoing synthesis of the donor specific antibody. Lastly, the efficacy of short term plasmapheresis in rapidly eliminating preformed anti-donor antibody will be studied in both CSA treated and control sensitized dogs. Clearly, demonstration of protection from accelerated rejection in presensitized hosts with current negative crossmatches has immediate clinical application by permitting this ever increasing number of patients to be successfully transplanted.
