Indirect presentation of allogeneic MHC antigen is an important pathway by which allografts are rejected and tolerance maintained by regulatory CD4(+) T cells. In this study HLA-A2 derived synthetic peptides were used to determine whether T cells of non-HLA-A2 renal graft recipients, which had been HLA-A2 mismatched to their organ donors, recognize some of the HLA-A2-derived peptides. Among the HLA-A2 mismatched patients, 60% recognized residues 56--69, 65--79, and 75--89. Peripheral blood lymphocytes derived from healthy individuals showed low reactivity towards allopeptides, indicating that sensitization towards HLA-A2 induced response towards HLA-A2 derived peptides. The response to the peptides was blocked by antibodies to HLA-DR, -DQ, and CD4. Depletion of antigen presenting cells abrogated response towards the allopeptides, confirming that the observed proliferation was mediated by the indirect pathway. Interestingly, although none of the HLA-A2 mismatched patients had any signs for either acute or chronic rejection, considerable response to allo-derived HLA-A2 was observed.