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 longstanding, successful strategy for inducing tolerance in experimental rodent transplantatio n models, can promote long-term acceptance of life-sustaining renal al lografts in rhesus monkeys with no maintenance immunosuppression. To investigate the immunological basis for heterogeneity in duration of l ong-term graft acceptance following infusion of the DR(-/dim) fraction of DBMC into RATG-treated rhesus monkeys, we examined the. relationsh ip of recipient-donor major histocompatibility class I and II DR match ing to the development of antidonor antibody-dependent cellular cytoto xicity (ADCC) and renal allograft survival. The findings indicate a re quirement for sharing one DR allele to achieve long-term graft accepta nce. The observed immunological consequence of DR sharing that correla ted with functional graft tolerance in this model was the suppression of early antidonor ADCC(+) IgG antibody responses, Significant associa tions were observed between graft survival and suppression of ADCC ant ibody (P<0.0005), graft survival and DR sharing (P<0.005), and DR shar ing and suppression of ADCC (P<0.02), Early antidonor ADCC antibody re sponses associated with failure to maintain graft tolerance and were m ost consistently directed to donor class I, The required one DR antige n sharing in DBMC-induced suppression of antidonor class I antibody su ggests a restriction for recipient DR, implying critical regulation of a response to donor antigen presented on recipient cells, We hypothes ize 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 exp ansion elicited by both the direct and indirect antigen presentation p athways.