A CD8 DE loop peptide analog prevents graft-versus-host disease in a multiple minor histocompatibility antigen-mismatched bone marrow transplantation model

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation
S ChoksiR Korngold

Abstract

Donor CD8(+) T cells can be potent mediators of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation to either major histocompatibility complex (MHC) class I-or multiple minor histocompatibility antigen-mismatched recipients. To develop small molecular inhibitors of CD8(+) T-cell activity, theoretical structural analysis of the human CD8 alpha molecule was previously used to identify potential functional surface epitopes that interact with the MHC class I molecule. The DE loop (p71-78) was identified as such a target region, and a panel of synthetic cyclized peptide mimics of this region were tested for their inhibitory effects on cytotoxic T lymphocyte activity in human cell-mediated lympholysis assays. Peptide 1109 (CKRLGDTFVC) was most effective at inhibiting specific target cell lysis. Accordingly, studies were conducted to determine whether there was sufficient cross-species homology in the DE loop region and its nonpolymorphic interactive site on the beta(2)-microglobulin domain of the MHC class I molecule to allow similar inhibition of murine CD8(+) cytotoxic T lymphocyte activity. On the basis of strong in vitro inhibitory activity of 1109 in the murine system, the capacity of the peptide...Continue Reading

References

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