title: Indirect recognition of donor HLA-DR peptides in organ allograft rejection.
abstract: 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.
authors.affiliation: College of Physicians and Surgeons of Columbia University, New York 10032, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.forename: A I
authors.initials: AI
authors.lastname: Colovai
authors.forename: S
authors.initials: S
authors.lastname: Tugulea
authors.forename: E F
authors.initials: EF
authors.lastname: Reed
authors.forename: P E
authors.initials: PE
authors.lastname: Fisher
authors.forename: D
authors.initials: D
authors.lastname: Mancini
authors.forename: E A
authors.initials: EA
authors.lastname: Rose
authors.forename: R
authors.initials: R
authors.lastname: Cortesini
authors.forename: R E
authors.initials: RE
authors.lastname: Michler
authors.forename: N
authors.initials: N
authors.lastname: Suciu-Foca
mesh_terms: D002478:Cells, Cultured; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D006684:HLA-DR Antigens / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D006650:Histocompatibility Testing; D006801:Humans; D007108:Immune Tolerance; D016056:Immunodominant Epitopes; D008213:Lymphocyte Activation; D008297:Male; D010455:Peptides / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D013997:Time Factors
chemical_list: D006684:HLA-DR Antigens; D016056:Immunodominant Epitopes; D010455:Peptides