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 resulting from antigen processing by antigen-presenting cells. In contrast to this indirect recognition, MHC molecules of foreign cells can be directly recognized by T cells. Direct recognition has for a long time been considered the only mechanism responsible for transplant rejection. Recent studies have provided evidence of a role of indirect recognition 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 allograft rejection in rats. Recipients were immunized before transplantation with synthetic donor MHC I peptides. The animals developed antibody and T-cell responses. Depending on the rat strain, peptide pretreatment 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 accelerated rejection (DA-->LEW; untreated controls 7.5 +/- 0.3 days, treated rats 5.1 +/- 0.2 days; P < 0.0002). Importantly, sensitization by indirect 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 peptides were derived. Although the immunization elicited a measurable immune response, it did not lead to accelerated rejection. We conclude that sensitization by indirect recognition is able to initiate an acute rejection even in recipients in which neither direct nor indirect recognition is effective, and that this effect is strain-dependent. The form in which the donor antigen is administered is decisive for the induction of rejection by indirect activation.