CHRONIC CARDIAC REJECTION IN THE LEW TO F344 RAT MODEL BLOCKADE OF CD28-B7 COSTIMULATION BY CTLA41G MODULATES T-CELL AND MACROPHAGE ACTIVATION AND ATTENUATES ARTERIOSCLEROSIS

CTLA4Ig, a fusion protein that blocks CD28-B7 costimulation, was Studi ed in a LEW to F344 rat model of chronic cardiac rejection. In rats tr eated with a single dose of CTLA4Ig (0.5 mg intraperitoneally) 2 d aft er transplantation, allografts survived significantly longer (> 70 d i n 64%) than in untreated controls or rats treated with control Ig (all rejected within 25 d). Only 25% of grafts from rats treated with a si ngle, high dose of cyclosporine A (25 mg/kg, 2 d after transplantation ) survived longer than 70 d. Reverse transcriptase PCR and immunostain ing analyses of tissue from 75-d, CTLA4Ig-treated allografts showed re duced expression of the T cell factor IFN-gamma and macrophage activat ion factors monocyte chemoattractant protein-1, inducible nitric oxide synthase, and galactose/N-acetylgalactosamine macrophage lectin, as w ell as TGF-beta. Grafts from longterm survivors (> 120 d) treated with CTLA4Ig showed significant reductions in the frequency and severity o f arterio sclerosis in comparison with cyclosporine A-treated rats. Th us, T cell activation is a proximal event in the cascade that culminat es in the arteriosclerosis of chronic rejection. Strategies for blocki ng T cell costimulation may help prevent chronic rejection in clinical transplantation.