Beneficial effect of glatiramer acetate (Copaxone) on immune modulation of experimental hepatic fibrosis

Amjad Horani, Nidal Muhanna, Orit Pappo, Alaa Melhem, Carlos E. Alvarez, Sarit Doron, Wehbi Wehbi, Karussis Dimitrios, Scott L. Friedman, Rifaat Safadi

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

While CD8 subsets activate hepatic fibrosis, natural killer (NK) cells exhibit antifibrotic activity. Glatiramer acetate (GA) is an immune modulator for multiple sclerosis. We assessed the potential impact of GA on mouse hepatic fibrogenesis. Hepatic fibrosis was induced in C57BL/6 mice by intraperitoneal administration of carbon tetrachloride (CCl4) for 6 wk. During the last 2 wk, animals were also treated with either GA (200 μ/day ip) or medium and compared with naive and fibrotic mice (8 animals/group). GA markedly attenuated fibrosis without altering reactive oxygen species production. By morphometric measurement of Sirius redstained tissue sections, the relative fibrosis area decreased from 5.28 ± 0.32% (mean ± SE) in the untreated CCl4 group to 2.01 ± 0.28% in CCl 4+GA-treated animals, compared with 0.38 ± 0.07% in naive mice. α-Smooth muscle actin immunoblotting and mRNA expression revealed a similar pattern. Serum aminotransferase and Ishak-Knodell necroinflammatory score were markedly elevated, to the same extent, in both CCl 4-treated groups. Fibrosis induction was associated with significant increase in CD8 subsets and decrease in CD4 T cells. After GA treatment, however, NK content, CD4+CD25+FoxP3+ cells, hepatic expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and apoptosis of hepatic stellate cells were all increased. Serum interleukin (IL)-10 levels markedly rose, whereas IL-4 fell. In vitro activation of human hepatic stellate cells cocultured with hepatitis C virus-derived peripheral blood lymphocytes decreased when lymphocytes were preincubated with GA before coculture. In an animal model of hepatic fibrosis, GA has an antifibrotic effect associated with decreased CD8 cells and reduced serum IL-4 levels and increased NK cells, CD4+CD25+FoxP3+ cells, TRAIL, and elevated serum IL-10 levels.

Original languageEnglish
Pages (from-to)G628-G638
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume292
Issue number2
DOIs
StatePublished - Feb 2007

Keywords

  • Cirrhosis
  • Immune modulation
  • Liver injury
  • Lymphocytes
  • Stellate cell

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