INDIRECT RECOGNITION OF DONOR HLA-DR PEPTIDES IN ORGAN ALLOGRAFT-REJECTION

To determine whether indirect allorecognition is involved in heart all ograft rejection T cells obtained from peripheral blood and graft biop sy tissues were expanded in the presence of IL-2 and tested in limitin g dilution analysis (LDA) for reactivity to synthetic peptides corresp onding to the hypervariable regions of the mismatched HLA-DR antigen(s ) of the donor, Serial studies of 32 patients showed that T cell react ivity to donor allopeptides was strongly associated with episodes of a cute rejection. The frequency of allopeptide reactive T cells was 10-5 0-fold higher in the graft than in the periphery indicating that T cel ls activated via the indirect allorecognition pathway participate acti vely in acute allograft rejection. In recipients carrying a graft diff ering by two HLA-DR alleles the response appeared to target only one o f the mismatched antigens of the donor, Indirect allorecognition was r estricted by a single HLA-DR antigen of the host and directed against one immunodominant peptide of donor HLA-DR protein. However, intermole cular spreading was demonstrated in patients with multiple rejection e pisodes by showing that they develop allopeptide reactivity against th e second HLA-DR antigen. These data imply that early treatment to supp ress T cell responses through the indirect pathway of allorecognition, such as tolerance induction to the dominant donor determinant, may be required to prevent amplification and perpetuation of the rejection p rocess.