Kd. Chavin et al., ANTI-CD2 MONOCLONAL-ANTIBODIES SYNERGIZE WITH FK506 BUT NOT WITH CYCLOSPORINE OR RAPAMYCIN TO INDUCE TOLERANCE, Transplantation, 57(5), 1994, pp. 736-740
CsA, FK506, and rapamycin prolong allograft survival; however, each ha
s significant associated side effects at therapeutic doses. Anti-CD2 m
Abs also prolong survival but without toxicity. We tested whether alph
a CD2 mAbs in combination with subtherapeutic immunosuppression could
prolong allograft survival in a synergistic fashion. C57BL/6 (H-2(b))
mouse hearts were transplanted to CBA (H-2(k)) mice in a heterotopic,
nonvascularized cardiac allograft model. Recipients received immunosup
pressants intraperitoneally for 14 days and/or alpha CD2 mAb intraveno
usly for 2 days starting at the time of grafting. Survival was determi
ned by electrocardiogram monitoring. Anti-CDa alone prolonged survival
to 22.4+/-1.0 days versus 13.4+/-0.5 days for untreated controls (P<0
.05), while low dose FK506 minimally prolonged survival to 16.7+/-0.7
days (P<0.057). However, FK506 plus alpha CD2 resulted in synergistic
prolongation of graft survival to 28.0+/-2.1 days. Several doses of Cs
A and rapamycin in combination with alpha CD2 did not prolong survival
over alpha CD2 administered alone. A 60-day course of low dose FK506
plus alpha CD2 resulted in indefinite graft survival (> 165 days). The
se animals were tolerant since they accepted a second donor-specific g
raft. CTL and MLR activity in long term recipients were normal to both
donor-specific and third party alloantigen. The combination of alpha
CD2 with low dose FK506 is synergistic in prolonging cardiac allograft
survival, while combinations with CsA and rapamycin are not. Continuo
us administration of low dose FK506 plus alpha CD2 results in a state
of tolerance. This suggests that FK506 acts at a different locus in al
lograft immunity compared with the other immunosuppressants and this m
ay be related to the alternative CD2 T cell activation pathway.