Allospecific T lymphocytes mediate graft rejection through specific, direct or indirect, recognition of processed determinants of foreign MHC class I molecules. Small synthetic peptides derived from highly conserved sequences of the alpha 1 helix of the first domain of certain MHC class I molecules have been shown to inhibit CTL responses in vitro and to prolong graft survival in rats when combined with subtherapeutic doses of cyclosporine. Here, we report that the survival of LEW.1W heart allografts was significantly prolonged when transplanted into congenic LEW.1A recipients treated only with a peptide corresponding to residues 75-84 of the human HLA-B7-01 molecule (B7.75-84) before transplantation. The experimental value for mean survival time (+/- SD) in untreated recipients was 13 +/- 6 days and in peptide-treated recipients was 42 +/- 27 days (P < 0.002). A total of 64% of treated recipients had a functioning graft at 30 days, while grafts were rejected in all rats belonging to the control group within this time. Within graft-infiltrating leukocytes (GIL) in B7.75-84-treated animals, the proportion of T cells was significantly lower and that of CD5-/TCR alpha beta-/CD16-/CD8+ and MHC class II+ cells concomitantly increased, as compared with nontreated animals. GIL from B7.75-84-treated animals also exhibited a dramatic decrease (approximately 70%) of allospecific and spontaneous (NK) cytotoxic activity, whereas their proliferation and IL-2 production were similar in both experimental groups. The IFN-gamma, IL-2, and IL-10 mRNA levels from GIL from peptide-treated recipients were similar to levels of controls, reflecting a state of activation of GIL. Perforin and granzyme A mRNA, the level of which may be modulated parallel to impaired cytotoxic functions, were at similar levels in both experimental groups. These data demonstrate that B7.75-84 significantly prolongs graft survival in LEW.1A rats when given as a single agent and suggests that a specifically decreased cytotoxic response (allospecific and spontaneous) plays a major role.