Combined anti-CD2 and anti-CD3 receptor monoclonal antibodies induce donor-specific tolerance in a cardiac transplant model.

Abstract

Administration of mAb against either the CD2 or CD3 receptor prolongs graft survival in CBA recipients in a heterotopic, nonvascularized cardiac transplant model, whereas the combination of mAb produces indefinite survival. Combined alpha-CD2 plus alpha-CD3 mAb synergistically prolonged allograft survival indefinitely for C57BL/6 donor hearts (> 150 vs 13.4 +/- 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 allografts were rejected in a first set fashion (14.2 +/- 0.5 days). Anti-CD2 mAb of other epitopic specificities and isotypes demonstrate equivalent immunosuppressive capacity. The combination of mAb resulted in indefinite graft survival in other strain combinations. Therefore, these results are not restricted to a particular alpha-CD2 mAb or MHC combination. Combinations of alpha-CD2 plus mAb with specificities other than to CD3 did not result in tolerance, showing that the CD2-CD3 interaction was critical for tolerance induction. CTL and MLR responses from tolerant animals were normal both to H-2b and H-2d stimulators, indicating that clonal deletion of effector T cells did not occur. Adoptive transfer of naive recipient type cells broke tolerance, showing that graft adaptation was not the major determinant of tolerance maintenance. Flow cytometric analysis demonstrated that tolerance was not associated with deletion of T cells. The results imply that the mechanism of tolerance induction is related to suppression and/or anergy of helper and effector cells at the time of allografting, whereas maintenance of tolerance is associated with anergy in the Th cell compartment.