Prolongation of Cardiac Graft Survival with Anti-CD4Ig Plus hCTLA4Ig in Primates

• Published in: The Journal of surgical research Vol. 76; no. 2; pp. 174 - 178
• Main Authors: Krieger, Nancy R., Yuh, David, McIntyre, W.Burley, Flavin, Thomas F., Yin, Dengping, Robbins, Robert, Fathman, C.Garrison
• Format: Journal Article Conference Proceeding
• Language: English
• Published: New York, NY Elsevier Inc 01-05-1998; Elsevier
• Subjects: Abatacept; allograft survival; Animals; anti-CD4; Antibodies, Monoclonal - therapeutic use; Antigens, CD; Antigens, Differentiation - analysis; Antigens, Differentiation - immunology; Biological and medical sciences; cardiac transplant; CD4 Antigens - immunology; CTLA-4 Antigen; CTLA4Ig; Graft Survival; Heart Transplantation; Immunoconjugates; Immunomodulators; Immunosuppression - methods; Immunotherapy; Macaca mulatta; Male; Medical sciences; Pharmacology. Drug treatments; Rats; Rats, Inbred ACI; Rats, Inbred Lew; rhesus monkeys; CTLA4Ig; cardiac transplant; rhesus monkeys; anti-CD4; allograft survival; Heart; Rat; Antibody; Rodentia; Homograft; Heterotopic; Survival; Vertebrata; Mammalia; Animal; Immunotherapy; Graft; Influence; Immunosuppressive agent
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1006/jsre.1998.5318

Background.The aim of this study was to determine whether the use of combined immunotherapy with a brief course of humanized anti-CD4Ig and hCTLA4Ig would prolong heterotopic cardiac allograft survival in primates (rhesus monkeys). This model was based on work in “high responder” rats where a brief course of depletive anti-CD4 mAb plus hCTLA4Ig was successful in inducing transplantation tolerance.
Methods.Heterotopic cardiac transplants were performed in rhesus recipients. Donor/recipient pairs between groups were confirmed to be reactive prior to transplantation by MLR matching. Humanized anti-CD4Ig, a recently developed 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 and 2 for the first recipient and days 0, 2, 4, and 6 for the second recipient. 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 hCTLA4Ig 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 × 4, 11 days × 1). FACS analysis demonstrated CD4 depletion of anti-CD4 treated animals to <2% on posttransplant day 1. The CD4+T cells gradually repopulated to 50–70% pretransplant levels just prior to rejection. No adverse responses (fever, tachypnea, tachycardia, infections) were observed.
Conclusions.These are the first results demonstrating that a brief course of combined specific induction immunotherapy with humanized anti-CD4Ig plus hCTLA4Ig, in the absence of adjuvant posttransplant immunosuppression, was well tolerated and resulted in marked prolongation of cardiac allograft survival in primates.