INDUCTION OF ALLOGRAFT NONRESPONSIVENESS AFTER INTRATHYMIC INOCULATION WITH DONOR CLASS-I ALLOPEPTIDES - I - CORRELATION OF GRAFT-SURVIVAL WITH ANTIDONOR IGG ANTIBODY SUBCLASSES

We have recently demonstrated that cardiac allograft rejection in the PVG,R8-to-PVG,1U rat strain combination involves the recognition of a isolated class I (RT1.A(a)) molecules as peptides in the context of th e recipient MHC molecules, Three synthetic peptides (Pi, P2, and P3) c orresponding to the alpha-helices of the RT1.A(a) molecule served as T -cell epitopes for graft rejection, In this study, we demonstrate that two of these peptides (P2 and P3) are sufficient to induce immune non responsiveness (median survival time >237 days) to cardiac allografts when presented to the recipient immune system in the thymus 7 days bef ore transplantation. This effect was time dependent, as intrathymic in oculation 60 days before transplantation did not prolong graft surviva l (median survival time=12 days), Previous studies have demonstrated a critical role for alloantibody responses in mediating graft rejection in this rat strain combination, We, therefore, studied the role alloa ntibody responses may play in the observed immune nonresponsiveness, T he titers of alloantibody in serum samples harvested from graft recipi ents at different times after transplantation were measured, We used r ecipient primary aortic endothelial cells genetically manipulated to e xpress the donor RT1.A(a) molecule as targets in an enzyme-linked immu nosorbent assay, High titers of anti-RT1.A(a) IgM antibody were detect ed in unmanipulated controls at the time of graft rejection, The IgM a ntibody switched to high IgG titers in intrathymically inoculated rats with accelerated or delayed rejection, Graft rejection in intrathymic ally manipulated recipients that had achieved a transient state of imm unological nonresponsiveness correlated with higher titers of the IgG2 b alloantibody, In marked contrast, the long-term graft survivors expr essed undetectable or low levels of the IgG2b antibody and moderate to high levels of the IgG1 and IgG2a subclasses, These data suggest that the IgG2b alloantibody may contribute to the rejection reaction, wher eas IgG1 and IgG2a may be involved in active enhancement of graft surv ival.