HLA Peptide-mediated Strategies for Modulation of Cellular and Humoral Immune Response in Transplantation

New insights into the mechanisms of allorecognition (direct and indirect pathways) and the molecular interactions of the T cell receptor (TCR) with the human leukocyte antigen (HLA)-peptide complex on antigen presenting cells (APCs) have stimulated research into peptide-based strategies of immunosuppression. Although direct recognition of allogeneic molecules on APCs of the graft may induce a state of tolerance, the continuous presentation of processed alloantigens by professional APCs of the recipient does not allow the same phenomenon to occur. It has been demonstrated that indirect recognition of allogeneic HLA molecules and spread of the T cell alloreactivity to other epitopes within the allogeneic HLA molecules might play an important role in provoking graft rejection. Tolerance induction to the dominant (immunogenic) donor determinants, achieved by administration of antagonist (nonimmunogenic) synthetic peptide-based treatments, represents a potential effective strategy for blocking indirect alloresponse and ensuring long-term graft survival. On the basis of this knowledge, computer based rational prediction and mapping of the immunogenic and non-immunogenic determinant on HLA molecules presented during the course of transplantation is a powerful and promising strategy. Moreover, design of analogues / antagonists of epitopes critical for normal T cell activation could also be used. Thus, peptides derived from various regions of HLA class I and II molecules and structure-based peptides have demonstrated immunomodulatory effects both in vitro and in vivo. Early downregulation of the antigen specific indirect alloreactivity, using the various strategies discussed in this review, may allow long-term survival of human allografts without the need of HLA-compatibility and without the continuous recipient immunosupression.