NOVEL IMMUNOTHERAPEUTIC STRATEGIES USING MHC DERIVED PEPTIDES

Organ transplantation is now the treatment of choice for end stage org an failure. The ultimate goal in transplantation remains the developme nt of strategies to induce specific tolerance to the allograft. The ma jor histocompatibility complex (MHC) antigens are the principal target s of the immune response to allografts and T cell recognition of allo- MHC is the initial event which initiates allograft rejection. The avai lability of sequences of MHC genes in mice, rats and humans has made i t possible to prepare synthetic peptides for the study of the role of MHC peptides in allorecognition and tolerance induction. New evidence confirms that there are at least two distinct, but not necessarily mut ually exclusive, pathways of allorecognition. In the so-called ''direc t'' pathway T cells recognize intact allo-MHC molecules on the surface of donor cells. These MHC molecules contain an array of endogenous pe ptides bound in their antigen presentation groove. In the ''indirect'' pathway, T cells recognize specific processed alloantigen presented a s peptides in the context of self MHC by antigen-presenting cells (APC s). In addition, there is ample evidence that synthetic MHC peptides c an immunomodulate the alloimmune response both in vitro and in vivo, a nd that potent allo-tolerance can be induced with synthetic MHC peptid es. Two types of effects mediated by synthetic MHC peptides have been demonstrated: (1) suppression of the alloimmune response by relatively non-polymorphic peptides and (2) antigen-specific unresponsiveness in duced by polymorphic peptides. The mechanisms mediating the immunomodu latory effects of synthetic class I and class II MHC peptides and the potential for clinical applications are reviewed.