Jm. Thomas et al., THE FACILITATING EFFECT OF ONE-DR ANTIGEN SHARING IN RENAL-ALLOGRAFT TOLERANCE INDUCED BY DONOR BONE-MARROW IN RHESUS-MONKEYS, Transplantation, 59(2), 1995, pp. 245-255
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.