Indirect recognition of donor HLA-DR peptides in organ allograft rejection

J Clin Invest. 1996 Sep 1;98(5):1150-7. doi: 10.1172/JCI118898.


To determine whether indirect allorecognition is involved in heart allograft rejection T cells obtained from peripheral blood and graft biopsy tissues were expanded in the presence of IL-2 and tested in limiting dilution analysis (LDA) for reactivity to synthetic peptides corresponding to the hypervariable regions of the mismatched HLA-DR antigen(s) of the donor. Serial studies of 32 patients showed that T cell reactivity to donor allopeptides was strongly associated with episodes of acute rejection. The frequency of allopeptide reactive T cells was 10-50-fold higher in the graft than in the periphery indicating that T cells activated via the indirect allorecognition pathway participate actively in acute allograft rejection. In recipients carrying a graft differing by two HLA-DR alleles the response appeared to target only one of the mismatched antigens of the donor. Indirect allorecognition was restricted by a single HLA-DR antigen of the host and directed against one immunodominant peptide of donor HLA-DR protein. However, intermolecular spreading was demonstrated in patients with multiple rejection episodes by showing that they develop allopeptide reactivity against the second HLA-DR antigen. These data imply that early treatment to suppress 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 process.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cells, Cultured
  • Female
  • Graft Rejection / immunology*
  • HLA-DR Antigens / immunology*
  • Heart Transplantation / immunology*
  • Histocompatibility Testing
  • Humans
  • Immune Tolerance
  • Immunodominant Epitopes
  • Lymphocyte Activation
  • Male
  • Peptides / immunology*
  • T-Lymphocytes / immunology*
  • Time Factors


  • HLA-DR Antigens
  • Immunodominant Epitopes
  • Peptides