ALLOGRAFT SURVIVAL FOLLOWING IMMUNIZATION WITH MEMBRANE-BOUND OR SOLUBLE PEPTIDE MHC CLASS-I DONOR ANTIGENS - FACTORS RELEVANT FOR THE INDUCTION OF REJECTION BY INDIRECT RECOGNITION

T cells recognize foreign antigens in the form of peptide fragments re sulting from antigen processing by antigen-presenting cells. In contra st to this indirect recognition, MHC molecules of foreign cells can be directly recognized by T cells. Direct recognition has for a long tim e been considered the only mechanism responsible for transplant reject ion. Recent studies have provided evidence of a role of indirect recog nition in rejection. In the current series of experiments, we studied the influence of indirect alloactivation, induced either by donor MHC class I peptides or by membrane-bound MHC I molecules, on heart allogr aft rejection in rats. Recipients were immunized before transplantatio n with synthetic donor MHC I peptides. The animals developed antibody and T-cell responses. Depending on the rat strain, peptide pretreatmen t either had no effect on graft survival (DA-->PVG; untreated controls 8.5 +/- 0.6 days, treated rats 9.5 +/- 0.6 days) or led to accelerate d rejection (DA-->LEW; untreated controls 7.5 +/- 0.3 days, treated ra ts 5.1 +/- 0.2 days: P < 0.0002). Importantly, sensitization by indire ct activation induced acute rejection in a donor-recipient combination (LEW.1A-->LEW.1WR2) in which neither direct nor indirect recognition led to rejection (untreated controls > 400 days, pretreated rats 15 +/ - 4.2 days). Another group of animals was immunized with allogeneic or congenic erythrocytes carrying the MHC I antigen from which the pepti des were derived. Although the immunization elicited a measurable immu ne response, it did not lead to accelerated rejection. We conclude tha t sensitization by indirect recognition is able to initiate an acute r ejection even in recipients in which neither direct nor indirect recog nition is effective. and that this effect is strain-dependent. The far m in which the donor antigen is administered is decisive for the induc tion of rejection by indirect activation.