LIMITED T-CELL RESPONSE TO DONOR MHC PEPTIDES DURING ALLOGRAFT-REJECTION - IMPLICATIONS FOR SELECTIVE IMMUNE THERAPY IN TRANSPLANTATION

Previously, we have demonstrated that during allograft rejection, MHC molecules of the donor are processed and presented to alloreactive CD4 (+) T lymphocytes in the form of peptides associated with the MHC clas s II molecules of the recipient. There is an increasing body of eviden ce that this indirect pathway of allorecognition may play a major role in allograft rejection. Herein, we have used a series of overlapping MHC peptides progressing along the sequence of the donor MHC molecule in single residue steps. We have mapped all potential MHC Ag determina nts to which T cell responses could be generated after s.c. injection of allogeneic splenocytes. We have shown that splenic T cell prolifera tive responses to the beta 1 domains of donor A(k), A(d), and A(s) mou se MHC class II molecules were directed toward a single immunodominant determinant in each of three donor/recipient combinations. Interestin gly, after allogeneic spleen cell transplantation, an additional deter minant on donor MHC could be detected in the draining lymph nodes. Thi s result shows that the fine specificity of T cell response to donor t ransplantation Ags can differ between lymphoid organs. Then, we invest igated whether limitation of T cell response to donor MHC peptides app lies to the clinical situation of a graft. We have shown that after an allogeneic skin graft, self-restricted alloreactive T cells prolifera ted to the same determinant on the donor MHC molecule. These results i ndicate that immune intervention, such as tolerance induction to the d ominant T cell determinant on donor MHC molecules, may be developed fo r the prevention of allograft rejection.