A synthetic dimeric HLA class I peptide inhibits T cell activity in vitro and prolongs allogeneic heart graft survival in a mouse model.
A peptide derived from the alpha 1 domain of the human HLA class I heavy chain (amino acids 75-84; B2702.75-84) has been shown to inhibit human cytotoxic T and NK cell activity in a non-allele-restricted manner. In vivo, this peptide prolonged skin allograft survival in a murine model. Here we demonstrate prolongation of heart allograft survival in mice and extend the characterization of the immunomodulatory activity of B2702.75-84. Similar to what has been observed with retrovirus-derived peptides, the inhibitory capability of this peptide was increased when bound to a carrier protein. An increased immunomodulatory activity was also observed with the dimeric peptide B2702.84-75-75-84 or the multimeric B2702.75-84.MAP. This peptide not only inhibited cytotoxic T and NK cells but also anti-CD3-induced T cell proliferation as well as a mixed lymphocyte reaction (MLR). Flow cytometric analysis of T cells harvested from anti-CD3-stimulated spleen cell culture in the presence of B2702.84-75-75-84 showed decreased expression of activation markers (CD25, ICAM-1, Pgp-1, CD69) compared with untreated control cultures. The superior activity of B2702.84-75-75-84 could also be demonstrated in vivo. Administration of B2702.84-75-75-84 prolonged the survival of B6 (H2b) hearts in CBA (H2k) recipients to 15 +/- 2.7 (P = 0.0002 vs. control) days compared with 11.4 +/- 2.6 (P = 0.01) days in B2702.75-84 treated animals and 7.5 +/- 1.1 days in untreated controls. Administration of control peptides had no significant effect on allograft survival. In combination with a subtherapeutic dose of cyclosporine, B2702.75-84 induced long-term graft survival in 60% of recipients.
D000595:Amino Acid Sequence; D000818:Animals; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation; D015395:Histocompatibility Antigens Class I / Q000494:pharmacology*; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects*; D014184:Transplantation, Homologous
D015395:Histocompatibility Antigens Class I; D010446:Peptide Fragments