PROLONGATION OF ALLOGENEIC HEART GRAFT-SURVIVAL IN RATS BY ADMINISTRATION OF A PEPTIDE (AA-75-84) FROM THE ALPHA-1 HELIX OF THE FIRST DOMAIN OF HLA-B7-01

Allospecific T lymphocytes mediate graft rejection through specific, d irect or indirect, recognition of processed determinants of foreign MH C class I molecules. Small synthetic peptides derived from highly cons erved sequences of the alpha 1 helix of the first domain of certain MH C class I molecules have been shown to inhibit CTL responses in vitro and to prolong graft survival in rats when combined with subtherapeuti c doses of cyclosporine. Here, we report that the survival of LEW.1W h eart allografts was significantly prolonged when transplanted into con genic LEW.1A recipients treated only with a peptide corresponding to r esidues 75-84 of the human HLA-B7-01 molecule (B7.75-84) before transp lantation. The experimental value for mean survival time (+/-SD) in un treated recipients was 13+/-6 days and in peptide-treated recipients w as 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 b elonging to the control group within this time. Within graft-infiltrat ing leukocytes (GIL) in B7.75-84-treated animals, the proportion of T cells was significantly lower and that of CD5(-)/TCR alpha beta(-)/CD1 6(-)/CD8(+) and MHC class II+ cells concomitantly increased, as compar ed with nontreated animals. GIL from B7.75-84-treated animals also exh ibited a dramatic decrease (approximate to 70%) of allospecific and sp ontaneous (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 w ere similar to levels of controls, reflecting a state of activation of GIL. Perforin and granzyme A mRNA, the level of which may be modulate d parallel to impaired cytotoxic functions, were at similar levels in both experimental groups. These data demonstrate that B7.75-84 signifi cantly prolongs graft survival in LEW.1A rats when given as a single a gent and suggests that a specifically decreased cytotoxic response (al lospecific and spontaneous) plays a major role.