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

Mary E. Russell, Wayne W. Hancock, Enver Akalin, Africa F. Wallace, Troels Glysing-Jensen, Theresa A. Willett, Mohamed H. Sayegh

Research output: Contribution to journalArticlepeer-review

156 Scopus citations

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-γ and macrophage activation factors monocyte chemoattractant protein-1, inducible nitric oxide synthase, and galactose/N-acetylgalactosamine macrophage lectin, as well as TGF-β. Grafts from long-term 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.

Original languageEnglish (US)
Pages (from-to)833-838
Number of pages6
JournalJournal of Clinical Investigation
Volume97
Issue number3
DOIs
StatePublished - Feb 1 1996

Keywords

  • Arteriosclerosis
  • CD28
  • Cardiac transplantation
  • Macrophage activation

ASJC Scopus subject areas

  • Medicine(all)

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