Indirect recognition of donor HLA-DR peptides in organ allograft rejection.
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.
Liu
Z
Z
College of Physicians and Surgeons of Columbia University, New York 10032, USA.
Colovai
A I
AI
Tugulea
S
S
Reed
E F
EF
Fisher
P E
PE
Mancini
D
D
Rose
E A
EA
Cortesini
R
R
Michler
R E
RE
Suciu-Foca
N
N
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
D006684:HLA-DR Antigens; D016056:Immunodominant Epitopes; D010455:Peptides