PEPTIDES DERIVED FROM ALPHA-HELICES OF ALLOGENEIC CLASS-I MAJOR HISTOCOMPATIBILITY COMPLEX ANTIGENS ARE POTENT INDUCERS OF CD4(-CELL AND B-CELL RESPONSES AFTER CARDIAC ALLOGRAFT-REJECTION() AND CD8(+) T)

We studied the rejection of cardiac allografts in a rat strain combina tion (PVG.R8 to PVG.1U) disparate for a single class I MHC antigen (RT 1.A(a)) to test the extent by which this molecule is recognized as pep tides in association with recipient MHC molecules during graft rejecti on and the contribution of this recognition process to the rejection r eaction. Three synthetic peptides that correspond to the portions of a lpha-helices of the alpha 1 (P1, P2) and alpha 2 (P3) domains of the d onor RT1.A(a) molecule were used in this study. Splenocytes from heart allograft recipients at rejection responded in a proliferation assay to all 3 peptides and in a cytotoxic assay to peptides P1 and P2. The peptide-mediated proliferation and cytolytic reactions were blocked by antibodies against CD4/class II MHC and CD8 molecules. Serum from gra ft recipients at rejection contained significant titers of antibodies to peptides. Presensitization of graft recipients with the peptides re sulted in a marked increase in peptide-mediated T cell and antibody re sponses. Although all 3 peptides were effective in eliciting active im mune responses, the P3-mediated response was minimal when compared wit h those mediated by P1 and P2. Recipients presensitized with the pepti des rejected their grafts in 5 days compared with 6 days for unsensiti zed animals. Recipients presensitized with donor-irradiated splenocyte s and aortic endothelial cells, on the other hand, rejected their graf ts in 1 and 3 days, respectively, which suggests that immunization wit h the whole RT1.A(a) molecule is required to stimulate accelerated rej ection of the graft. This rejection was associated with high titers of donor cell-specific antibodies that exhibited moderate cross-reactivi ty with the peptides. Our results clearly demonstrate that (1) the don or RT1.A(a) molecule is recognized as peptides in the context of recip ient class I and class II MHC molecules during the rejection of heart allografts, and (2) peptides derived from this molecule are highly imm unogenic in that they contain epitopes recognized by CD4(+) and CD8(+) T cells and alloantibodies. Immune responses elicited by these peptid es, however, did not significantly affect the rate of rejection. These results suggest that acute rejection of allografts may be mediated pr imarily by the direct recognition of intact MHC molecules.