Role of donor and recipient antigen-presenting cells in priming and maintaining T cells with indirect allospecificity.
BACKGROUND
It has been suggested that the sensitization of recipient T lymphocytes against peptides derived from allogeneic major histocompatibility complex (MHC) antigens in the context of self-MHC molecules may contribute to the pathogenesis of chronic allograft rejection. The purpose of this study was to quantitate and characterize the indirect alloresponse in renal transplantation.


METHODS
An HLA-A2-negative patient whose A2-positive kidney transplant failed as a result of chronic rejection was selected for this study. T-cell clones were raised using a cocktail of peptides corresponding to polymorphic regions of the A2 sequence and studied by measuring their proliferation using [3H]thymidine incorporation. The presence in vivo of HLA-A2-specific T cells was assessed using limiting dilution analysis.


RESULTS
T-cell clones were specific for a single peptide of HLA-A2, residues 92-120, and restricted by HLA-DRB1*1502. The frequency of interleukin-2-secreting T cells specific for this A2 peptide was 1:86,000, only 2-fold lower than that measured against the recall antigen tetanus toxoid. Capitalizing on the similarity of the donor and recipient DR15 alleles (DRB1*1501 and 1502), the question was addressed as to how these T cells had been primed in vivo. Although the large majority of clones responded to A2 synthetic peptide presented by both DR15 alleles, only 3 of 10 clones responded to cells co-expressing DRB1*1501 and A2.


CONCLUSIONS
These data suggest that antigen presentation by recipient APCs is responsible for maintaining T cells with indirect allospecificity in vivo and that, in the context of partial DR matching, indirect presentation by the parenchymal cells of the graft may serve to induce tolerance in T cells with indirect allospecificity.
Frasca
L
L
Department of Immunology, ICSM, Hammersmith Hospital, London, United Kingdom.
Amendola
A
A
Hornick
P
P
Brookes
P
P
Aichinger
G
G
Marelli-Berg
F
F
Lechler
R I
RI
Lombardi
G
G
D000938:Antigen-Presenting Cells / Q000378:metabolism / Q000502:physiology*; D002461:Cell Line, Transformed; D002999:Clone Cells; D003429:Cross Reactions / Q000276:immunology; D000939:Epitopes; D006084:Graft Rejection / Q000503:physiopathology; D015234:HLA-A Antigens / Q000096:biosynthesis; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D007519:Isoantigens / Q000276:immunology*; D016030:Kidney Transplantation / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D014019:Tissue Donors; D019172:Transplantation Conditioning
D000939:Epitopes; D015234:HLA-A Antigens; D006684:HLA-DR Antigens; D007519:Isoantigens