ROLE OF INDIRECT ALLORECOGNITION IN EXPERIMENTAL LATE ACUTE REJECTION

Background. Late acute rejection affects up to 28% of renal allograft recipients and remains a major risk factor for late graft loss. As don or-origin antigen-presenting cells are depleted with time, T-cell reco gnition of donor-derived alloantigenic peptides presented by self anti gen-presenting cells (the ''indirect pathway'' of allorecognition) may play a key role in the initiation of late acute rejection episodes. M ethods. To test this hypothesis, we developed a clinically relevant ex perimental model in the rat (Wistar-Furth/Lewis) in which allograft re cipients received cyclosporine for 1 month after transplantation and w ere then allowed to reject the graft upon discontinuation of immunosup pression. Lymphocyte proliferation assays to synthetic class II MHC al lopeptides of donor origin and also to intact donor (Wistar-Furth) cel ls were performed at this time, The effector mechanisms studied includ ed delayed-type hypersensitivity (DTH) responses, lymphocyte-mediated cytotoxicity, and alloantibody production, Results. Lymphocytes from r ecipients undergoing late acute rejection had marked suppression of mi xed lymphocyte reaction proliferation to intact donor cells. Significa nt proliferation to donor-derived 25-mer polymorphic class II MHC allo peptides was elicited, however, In vivo, significant DTH responses wer e observed to both MHC allopeptides and intact Wistar-Furth cells, Rec ipient lymphocytes also exhibited significant killing of donor cells, although not third-party cells, and anti-donor alloantibodies were det ected by flow cytometry, Conclusion. Our results indicate that T cells primed via the indirect pathway are present during acute rejection th at occurs after discontinuation of cyclosporine, Mixed lymphocyte reac tivity is markedly reduced at this time, Furthermore, there is an asso ciation between such allopeptide-primed T cells and the elicitation of specific DTH responses and provision of help to B cells to produce al loantibodies and activation of CD8+ T cells to become effector cytotox ic cells.