SINGLE-DOSE ANTI-CD4 MONOCLONAL-ANTIBODY FOR INDUCTION OF TOLERANCE TO CARDIAC ALLOGRAFT IN HIGH-RESPONDER AND LOW-RESPONDER RAT STRAIN COMBINATIONS

Repeated administration of monoclonal antibodies (mAb) directed agains t the CD4 lymphocyte receptor may induce specific, long-lasting unresp onsiveness to fully MHC-mismatched cardiac allografts in rats without additional immunosuppression. We assessed the effect of a single dose of murine anti-rat depleting anti-CD4 mAb (OX-38)) on allograft surviv al in high- and low-responder rat strain combinations. Isogenic strain s of DA (RT1(avt)), PVG (RT1(c)), AUG (RT1(c)), and WF (RT1(u)) rats w ere used. Recipients in antibody treated groups mere given one dose of 5 mg/kg OX-38 mAb on the day of transplant, a dose which was shown to effectively deplete (or block) circulating CD4(+) T cells. Other grou ps mere treated for 10 days with cyclosporin A (CsA) and/or Linomide, a novel immunomodulator, which is the first compound able to fully eli minate the effect of CsA in the rat cardiac allograft model. The DA st rain was identified as a low-responder to the allogeneic haplotype RT1 (c) (PVG or AUG), but not to RT1(u) (WF), and developed true tolerance following RT1(c) grafting and OX-38 or low-dose CsA (5 mg/kg) inducti on, as verified by the response to retransplantation of a graft from t he same donor strain or a third-party challenge. PVC recipients of DA grafts were characterized by high response and only modest (OX-38; med ian 9.5 days) or moderate (CsA; 23.5 days prolongation of graft surviv al. Contrasting graft survival results were obtained in tile low-respo nder combination, either very early rejection (at 10 days) or permanen t graft survival (> 100 days). Linomide challenge affected CsA treatme nt in the high-responder combination but not tolerance induction in th e low-responder combination, or the effect of OX-38. It was concluded that in rat heart transplantation a single-dose anti-CD4 mAb therapy m ay induce permanent donor-specific unresponsiveness in a low-responder strain combination, and that anti-CD4 mAb seems to be unique among im munosuppressive agents while being resistent to challenge by Linomide.