ROLE OF DONOR AND RECIPIENT ANTIGEN-PRESENTING CELLS IN PRIMING AND MAINTAINING T-CELLS WITH INDIRECT ALLOSPECIFICITY

Background. It has been suggested that the sensitization of recipient T lymphocytes against peptides derived from allogeneic major histocomp atibility complex (MHC) antigens in the context of self-MHC molecules may contribute to the pathogenesis of chronic allograft rejection. The purpose of this study was to quantitate and characterize the indirect alloresponse in renal transplantation. Methods. An HLA-A2-negative pa tient whose A2-positive kidney transplant failed as a result of chroni c rejection was selected for this study, T-cell clones were raised usi ng a cocktail of peptides corresponding to polymorphic regions of the A2 sequence and studied by measuring their proliferation using [H-3]-t hymidine incorporation. The presence in vivo of HLA-A2-specific T cell s was assessed using limiting dilution analysis. Results. T-cell clone s were specific for a single peptide of HLA-A2, residues 92-120, and r estricted by HLA-DRB11502. The frequency of interleukin-2-secreting T cells specific for this AZ peptide was 1:86,000, only a-fold lower th an that measured against the recall antigen tetanus toroid. Capitalizi ng on the similarity of the donor and recipient DR15 alleles (DRE1150 1 and 1502), the question was addressed as to how these T cells had be en primed in vivo. Although the large majority of clones responded to A2 synthetic peptide presented by both DR15 alleles, only 3 of 10 clon es responded to cells co-expressing DRB11501 and A2. Conclusion. Thes e data suggest that antigen presentation by recipient APCs is responsi ble for maintaining T cells with indirect allospecificity in vivo and that, in the context elf partial DR matching, indirect presentation by the parenchymal cells of the graft may serve to induce tolerance in T cells with indirect, allospecificity.