The facilitating effect of one-DR antigen sharing in renal allograft tolerance induced by donor bone marrow in rhesus monkeys.
Infusion of donor bone marrow cells (DBMC), a long-standing, successful strategy for inducing tolerance in experimental rodent transplantation models, can promote long-term acceptance of life-sustaining renal allografts in rhesus monkeys with no maintenance immunosuppression. To investigate the immunological basis for heterogeneity in duration of long-term graft acceptance following infusion of the DR-/dim fraction of DBMC into RATG-treated rhesus monkeys, we examined the relationship of recipient-donor major histo-compatibility class I and II DR matching to the development of antidonor antibody-dependent cellular cytotoxicity (ADCC) and renal allograft survival. The findings indicate a requirement for sharing one DR allele to achieve long-term graft acceptance. The observed immunological consequence of DR sharing that correlated with functional graft tolerance in this model was the suppression of early antidonor ADCC+ IgG antibody responses. Significant associations were observed between graft survival and suppression of ADCC antibody (P < 0.0005), graft survival and DR sharing (P < 0.005), and DR sharing and suppression of ADCC (P < 0.02). Early antidonor ADCC antibody responses associated with failure to maintain graft tolerance and were most consistently directed to donor class I. The required one DR antigen sharing in DBMC-induced suppression of antidonor class I antibody suggests a restriction for recipient DR, implying critical regulation of a response to donor antigen presented on recipient cells. We hypothesize a DBMC tolerogenic mechanism in which presentation of donor class I peptide by a shared DR allele configuration allows a veto effect by DBMC. Thus DR sharing would allow DBMC veto cells to reduce clonal expansion elicited by both the direct and indirect antigen presentation pathways.
Department of Surgery, University Medical Center of Eastern North Carolina, Greenville 27834.
J M
JM
Thomas
K M
KM
Verbanac
J P
JP
Smith
J
J
Kasten-Jolly
U
U
Gross
L M
LM
Rebellato
C E
CE
Haisch
F M
FM
Carver
F T
FT
Thomas
D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D001483:Base Sequence; D016026:Bone Marrow Transplantation / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000276:immunology; D006684:HLA-DR Antigens / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D016030:Kidney Transplantation / Q000276:immunology*; D008253:Macaca mulatta; D008297:Male; D008969:Molecular Sequence Data; D011817:Rabbits; D014019:Tissue Donors
D006684:HLA-DR Antigens; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D007074:Immunoglobulin G