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.
Thomas
J M
JM
Department of Surgery, University Medical Center of Eastern North Carolina, Greenville 27834.
Verbanac
K M
KM
Smith
J P
JP
Kasten-Jolly
J
J
Gross
U
U
Rebellato
L M
LM
Haisch
C E
CE
Carver
F M
FM
Thomas
F T
FT
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