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 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-CD4mAb 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-CD4mAb, 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 x 4, 11 days x 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.
Department of Surgery, Stanford University Medical Center, California 94305, USA.
N R
NR
Krieger
D
D
Yuh
W B
WB
McIntyre
T F
TF
Flavin
D
D
Yin
R
R
Robbins
C G
CG
Fathman
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000032:analysis / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology*; D060908:CTLA-4 Antigen; D006085:Graft Survival; D016027:Heart Transplantation; D018796:Immunoconjugates; D007165:Immunosuppression Therapy / Q000379:methods*; D007167:Immunotherapy; D008253:Macaca mulatta; D008297:Male; D051381:Rats; D011912:Rats, Inbred ACI; D011917:Rats, Inbred Lew
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; D018796:Immunoconjugates; D000069594:Abatacept