Prolonged skin graft survival by administration of anti-CD80 monoclonal antibody with cyclosporin A

Costimulation via the B7/CD28 pathway is an important signal for the activa tion of T cells. Maximal inhibition of T-cell activation and the induction of alloantigen-specific nonresponsiveness in vitro was achieved using anti- CD80 monoclonal antibody (mAb) in combination with cyclosporin A (CsA). Bas ed on this knowledge, the efficacy of the prophylactic treatment of anti-CD 80 mAb and CsA on allogeneic skin graft survival was tested in a preclinica l rhesus monkey model. No side effects have been observed. Administration o f anti-CD80 mAb resulted in high mAb serum levels that decreased to undetec table values around day 7. At the same time, the anti-mouse antibody respon se started to develop. The anti-CD80 mAb bound to peripheral blood mononucl ear cells and was detectable in lymph node and grafted skin during the trea tment period. The skin graft survival time of untreated or suboptimally CsA -treated rhesus monkeys was 10 days. Treatment with CsA (blood levels of 10 0-160 ng/ml) in combination with anti-CD80 mAb (0.5 mg/kg) resulted in a si gnificantly increased skin graft survival time to 14 days. Eventually, skin grafts in all rhesus monkeys were rejected, which coincided with an increa se in helper and cytotoxic T-cell frequency and induction of an antibody re sponse directed against the donor antigens. Therefore, treatment of anti-CD 80 mAb in combination with CsA has significant immunosuppressive potency, b ut was unable to induce donor-specific nonresponsiveness in skin graft reci pients.