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 journalArticle

155 Citations (Scopus)

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
StatePublished - Feb 1 1996
Externally publishedYes

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Macrophage Activation
Arteriosclerosis
Inbred F344 Rats
T-Lymphocytes
Transplantation
Cyclosporine
Allografts
TCF Transcription Factors
Transplants
Acetylgalactosamine
Chemokine CCL2
Nitric Oxide Synthase Type II
Reverse Transcriptase Polymerase Chain Reaction
Galactose
Lectins
Survivors
Macrophages
Proteins

Keywords

  • Arteriosclerosis
  • Cardiac transplantation
  • CD28
  • Macrophage activation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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

In: Journal of Clinical Investigation, Vol. 97, No. 3, 01.02.1996, p. 833-838.

Research output: Contribution to journalArticle

Russell, Mary E. ; Hancock, Wayne W. ; Akalin, Enver ; Wallace, Africa F. ; Glysing-Jensen, Troels ; Willett, Theresa A. ; Sayegh, Mohamed H. / 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. In: Journal of Clinical Investigation. 1996 ; Vol. 97, No. 3. pp. 833-838.
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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-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.",
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