Indirect recognition of donor MHC class II antigens in human transplantation

To investigate the role of the indirect pathway of recognition in human allograft rejection, we have mapped the dominant T cell determinant of the HLA-DRβ1(*)0101 molecule presented by the DRβ1(*)1101 antigen. A synthetic peptide (pp 22-35) corresponding to the sequence of the dominant peptide determinant was used for testing the frequency of in vivo activated T cells in the graft and in the periphery. DRβ1(*)1101-positive patients carrying a heart allograft mismatched for the HLA-DR1 antigen showed no reactivity to pp 22-35 during quiescence. However, interleukin-2-responsive T cells, which were pp 22-35 specific, were found in the circulation prior to and at the time of acute and chronic rejection. The response of in vivo and in vitro activated T cells was inhibited at high concentrations of peptide 22-35. This data suggests that indirect recognition plays an important role in allograft rejection and that it can be abolished by high zone tolerance induction.