Minor histocompatibility antigens (HA) in humans and mice constitute a formidable barrier to successful transplantation by stimulating allograft rejection/dysfunction and graft versus host disease. These antigens are a major complication in clinical transplantation, requiring immunosuppression with its own complications. Strong cytolytic T lymphocyte (CTL) responses to immunodominant minor HA are not without virtue, however, since they may provide for successful graft-versus-leukemia responses in cases where dominant minor HA are restricted to hematopoietic cells. The studies proposed in this application are directed first toward understanding the molecular basis for recognition of minor HA with the mouse H4 peptide and identified mimotopes serving as the principal model. The proposed experiments will test the hypothesis that the positively charged amino acid in the H4 is the preeminent factor in controlling recognition by H4-specific T-cell receptors (TcRs) and the function of H4 as a dominant peptide.
Three specific aims are proposed. First, mutational analysis of H4 mimotopes and Kb molecules will be performed to identify the amino acids that are involved in mimotopes and Kb binding and TcR recognition. Second, the evolution of diversity of minor HA-specific TcRs in the in vivo response to multiple antigenic challenges and prolonged exposure to antigen will be investigated to evaluate the stability of TcR beta chain diversity. Third, the effects of opposing charged residues in minor HA peptides and specific TcRs on recognition and dominant antigen function in vivo and in vitro will be identified. This recognition of minor HA peptides by TcRs expressed by CTLs occurs in vivo under the umbrella of systems that process minor HA peptides and ultimately destroy allografts.
The final aims relate to the mechanisms of dominance and allograft rejection. The fourth specific aim is testing the hypothesis that dominance is based in the destruction of professional antigen presenting cells by dominant antigen-specific CTLs to the exclusion of presentation of dominated antigens.
The final aim i s the study of the effect of expression of the pleiotropic tumor necrosis factor-a cytokine on transcription in skin allografts from the time of transplants to the time of rejection to assess the participation of donor and recipient gene expression in the entire process.
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