Since most kidney transplant recipients are histoincompatible with donor tissues, recipients must be immunosuppressed to prevent graft rejection. Of the several immunosuppressive procedures currently favored, two are relatively new and particularly intriguing: 1) Cyclosporine (CsA) therapy, and 2) pre-operative donor-specific blood transfusions (DST). The in vivo mechanisms by which these procedures prevent or attenuate allograft rejection remain speculative. We propose a series of studies designed to quantitate T cell functions that develop at a graft site, and to identify the alterations in these functions induced by CsA and DST. These studies will employ an established murine allograft model, the sponge matrix allograft, to investigate 1) the composition of graft-infiltrating lymphoid populations at various times after graft implantation as determined by morphologic, histologic and serologic criteria, 2) the cytolytic activity and population size of cytolytic T cells which accumulate at the graft site at various times after graft implantation as detected by direct cytolysis and limiting dilution analysis, 3) the helper T cell activity which accumulates at the graft site at various times after graft implantation as determined by analysis of sponge effluents and sponge-infiltrate T cell products for various lymphokines (IL-2, IL-3, MAF, CSF), and by limiting dilution analysis of helper T cell frequency, 4) the identity of any suppressive activity which develops at the graft site during allograft rejection, 5) the T cell-mediated events which develop in sponge allografts from Class I or Class II MHC-disparate congenic recombinant donor-recipient combinations, 6) the influence of systematically administered Cyclosporine on the composition and T cell functions of allograft infiltrating cells, and 7) the influence of DST on the composition and T cell functions of allograft infiltrating cells. In part, these studies will serve as in vivo tests of hypotheses concerning allorecognition which have developed from in vitro studies. In addition, they should provide considerable information regarding the requisite in situ components of allograft rejection. Finally, they provide a practical experimental model with which in vivo effects of various immunosuppressive therapies can be determined. Information thus obtained may suggest ways to optimize existing immunosuppressive protocols and, perhaps, may suggest new, more effective immunotherapies.
