PROLONGATION OF CARDIAC GRAFT-SURVIVAL WITH ANTI-CD4IG PLUS HCTLA4IG IN PRIMATES

Background The aim of this study was to determine whether the use of c ombined immunotherapy with a brief course of humanized anti-CD4Ig and hCTLA4Ig would prolong heterotopic cardiac allograft survival in prima tes (rhesus monkeys). This model was based on work in ''high responder '' rats where a brief course of depletive anti-CD4 mAb plus hCTLA4Ig w as successful in inducing transplantation tolerance. Methods. Heteroto pic cardiac transplants were per formed in rhesus recipients. Donor/re cipient pairs between groups were confirmed to be reactive prior to tr ansplantation by;MLR matching. Humanized anti-CD4Ig, a recently develo ped anti-CD4 mAb, was given at a dose of 20 mg/kg i.v. on days -3, -2, -1, and 0. hCTLA4Ig was administered at 6 mg/kg/dose i.v. on days 0 a nd 2 for the first recipient and days 0, 2, 4, and 6 for the second re cipient. No further immunosuppression was administered. The treated (n = 2) or untreated (n = 5) recipients were followed for graft function by daily palpitation. Results. Treatment with anti-CD4Ig plus hCTLA4I g resulted in a significant prolongation of heart graft survival (42 d ays for the first recipient and 52 days for the second recipient) comp ared to untreated recipients (7 days x 4, 11 days x 1). FAGS analysis demonstrated CD4 depletion of anti-CD4 treated animals to <2% on postt ransplant day 1. The CD4(-) T cells gradually repopulated to 50-70% pr etransplant levels just prior to rejection. No adverse responses (feve r, tachypnea, tachycardia, infections) were observed. Conclusions. The se are the first results demonstrating that a brief course of combined specific induction immunotherapy with humanized anti-CD4Ig plus hCTLA 4Ig, in the absence of adjuvant posttransplant immunosuppression, was well tolerated and resulted in marked prolongation of cardiac allograf t survival in primates. (C) 1998 Academic Press.