Anti-CD2 monoclonal antibodies synergize with FK506 but not with cyclosporine or rapamycin to induce tolerance.

CsA, FK506, and rapamycin prolong allograft survival; however, each has significant associated side effects at therapeutic doses. Anti-CD2 mAbs also prolong survival but without toxicity. We tested whether alpha CD2 mAbs in combination with subtherapeutic immunosuppression could prolong allograft survival in a synergistic fashion. C57BL/6 (H-2b) mouse hearts were transplanted to CBA (H-2k) mice in a heterotopic, non-vascularized cardiac allograft model. Recipients received immunosuppressants intraperitoneally for 14 days and/or alpha CD2 mAb intravenously for 2 days starting at the time of grafting. Survival was determined by electrocardiogram monitoring. Anti-CD2 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 CsA 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). These animals were tolerant since they accepted a second donor-specific graft. 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. Continuous administration of low dose FK506 plus alpha CD2 results in a state of tolerance. This suggests that FK506 acts at a different locus in allograft immunity compared with the other immunosuppressants and this may be related to the alternative CD2 T cell activation pathway.