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Research Article Free access | 10.1172/JCI118483

Chronic cardiac rejection in the LEW to F344 rat model. Blockade of CD28-B7 costimulation by CTLA4Ig modulates T cell and macrophage activation and attenuates arteriosclerosis.

M E Russell, W W Hancock, E Akalin, A F Wallace, T Glysing-Jensen, T A Willett, and M H Sayegh

Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, MA 02115, USA. russell@cvlab.harvard.edu.

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Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, MA 02115, USA. russell@cvlab.harvard.edu.

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Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, MA 02115, USA. russell@cvlab.harvard.edu.

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Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, MA 02115, USA. russell@cvlab.harvard.edu.

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Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, MA 02115, USA. russell@cvlab.harvard.edu.

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Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, MA 02115, USA. russell@cvlab.harvard.edu.

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Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, MA 02115, USA. russell@cvlab.harvard.edu.

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Published February 1, 1996 - More info

Published in Volume 97, Issue 3 on February 1, 1996
J Clin Invest. 1996;97(3):833–838. https://doi.org/10.1172/JCI118483.
© 1996 The American Society for Clinical Investigation
Published February 1, 1996 - Version history
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Abstract

CTLA4Ig, a fusion protein that blocks CD28-B7 costimulation, was studied in a LEW to F344 rat model of chronic cardiac rejection. In rats treated with a single dose of CTLA4Ig (0.5 mg intraperitoneally) 2 d after transplantation, allografts survived significantly longer ( > 70 d in 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 single, high dose of cyclosporine A (25 mg/kg, 2 d after transplantation) survived longer than 70 d. Reverse transcriptase PCR and immunostaining analyses of tissue from 75-d, CTLA4Ig-treated allografts showed reduced expression of the T cell factor IFN-gamma and macrophage activation factors monocyte chemoattractant protein-1, inducible nitric oxide synthase, and galactose/N-acetylgalactosamine macrophage lectin, as well as TGF-beta. Grafts from longterm survivors ( > 120 d) treated with CTLA4Ig showed significant reductions in the frequency and severity of arteriosclerosis in comparison with cyclosporine A-treated rats. Thus, T cell activation is a proximal event in the cascade that culminates in the arteriosclerosis of chronic rejection. Strategies for blocking T cell costimulation may help prevent chronic rejection in clinical transplantation.

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