Prolongation of cardiac graft survival with anti-CD4Ig plus HCTLA4Ig in primates

The aim of this study was to determine whether the use of combined immunotherapy with a brief course of anti-CD4-Ig and hCTLA4-Ig would prolong heterotopic cardiac allograft survival in primates. This model was based on our previous study of ôhigh responderö rats where a brief course of depletive anti-CD4 mAb plus hCTLA4-Ig successfully induced tolerance. Heterotopic cardiac transplants were performed in MLR mismatched rhesus recipients. A recently developed humanized anti-CD4 mAb, was given at a dose of 20 mg/kg iv on days -3, -2, -1, and 0. hCTLA4-Ig was given at 6 mg/kg iv on days 0 and 2 for the first recipient, and days 0, 2, 4, and 6 for the second recipient. No further immunoBuppression was given. The treated (n=2) or untreated (n=5) recipients were followed for graft function by daily palpation. Treatment with anti-CD4-Ig plus hCTLA4-Ig resulted in a significant prolongation of heart graft survival (42 days for the first recipient and 52 days for the second recipient) compared to untreated recipients (7 days). FACS analysis demonstrated CD4 depletion of treated animals to <2% on post-transplant day 1. The CD4+ T cells gradually repopulated to 50-70% pretransplant levels prior to rejection. No adverse responses were observed. These are the first results demonstrating that a brief course of combined specific induction immunotherapy with anti-CD4-Ig plus hCTLA4-Ig, in the absence of adjuvant post-transplant immunosuppression, was well tolerated and resulted in marked prolongation of cardiac allograft survival in primates.