COMBINED ANTI-CD2 AND ANTI-CD3 RECEPTOR MONOCLONAL-ANTIBODIES INDUCE DONOR-SPECIFIC TOLERANCE IN A CARDIAC TRANSPLANT MODEL

Administration of mAb against either the CD2 or CD3 receptor prolongs graft survival in CBA recipients in a heterotopic, nonvascularized car diac transplant model, whereas the combination of mAb produces indefin ite survival. Combined alpha-CD2 plus alpha-CD3 mAb synergistically pr olonged allograft survival indefinitely for C57BL/6 donor hearts (>150 vs 1 3.4 +/- 0.5 days for controls, p < 0.001, Wilcoxon's sign rank). All second donor-specific C57BL/6 allografts survived >100 days (p < 0.001) without any additional immunosuppression. Third-party BALB/c al lografts were rejected in a first set fashion (14.2 +/- 0.5 days). Ant i-CD2 mAb of other epitopic specificities and isotypes demonstrate equ ivalent immunosuppressive capacity. The combination of mAb resulted in indefinite graft survival in other strain combinations. Therefore, th ese results are not restricted to a particular alpha-CD2 mAb or MHC co mbination. Combinations of alpha-CD2 plus mAb with specificities other than to CD3 did not result in tolerance, showing that the CD2-CD3 int eraction was critical for tolerance induction. CTL and MLR responses f rom tolerant animals were normal both to H-2b and H-2d stimulators, in dicating that clonal deletion of effector T cells did not occur. Adopt ive transfer of naive recipient type cells broke tolerance, showing th at graft adaptation was not the major determinant of tolerance mainten ance. Flow cytometric analysis demonstrated that tolerance was not ass ociated with deletion of T cells. The results imply that the mechanism of tolerance induction is related to suppression and/or anergy of hel per and effector cells at the time of allografting, whereas maintenanc e of tolerance is associated with anergy in the Th cell compartment.