The inductionof specific immunologic unresponsiveness is one of the major goals in solid organ transplantation. The advent of new, non-cytotoxic immunosuppressive drugs such as cyclosporine (CsA), Rapamycin (RAP) and FK506 with their ability to induce transplantation tolerance after a limited course of therapy in some animal transplant systems has generated considerable enthusiasm. The mechanisms accounting for solid organ allograft tolerance after immunosuppressive therapy with these drugs remains ill defined. In addition, CsA and apparently FK506 inhibit the clonal deletion of MHC class II specific autocytotoxic T-cell clones. Based on preliminary studies that document the presence of autoreactive T-cells in CsA treated animals, it is tempting to speculate that these autoreactive T-cells are in fact a major cellular component of the immunologic basis of tolerance to solid grafts induced by CsA. The MHC class II specific autoreactive T-cells would recognize and lyse alloresponsive mature T-cells which express class II antigen in response to an allograft. The elimination of allograft responsive cells would lead to a peripheral clonal reduction or clonal elimination. Further, this mechanism would mimic the non-specific """"""""suppressor"""""""" cell phase observed after immunosuppressive therapy. The planned studies propose to examine this hypothesis in a pre- clinical rat,MHC disparate, heart allograft model. Initially, the ability of CD8+ and CD4+ effector cells which express the V- beta 8 T- cell receptor determinant marking autoreactive cells from animals with autoimmune graft-versus-host disease will be assessed for their ability toprolong heart allograft survival in adoptive transfer studies. Similarly, these cells which can be detected in normal or solid organ allografted rats treated with CsA will be evaluated for their role in allograft tolerance: 1) the effect of these cells on the prolongation of allograft survival will be determined and 2) the effect of V-beta-8 specific antibody administration on tolerance induction will be assessed. Additional studies plan to assess if the prolongation of allograft survival requires both the CD4+ and CD8+ autoreactive T- cells subsets and address if these cells mediate a peripheral clonal deletion of allograft responsive cells.
