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

¹Liver and Gastroenterology Units, Division of Medicine, ²Pathology Department, and ³Division of Neurology, Hadassah University Hospital, Jerusalem, Israel; and ⁴Division of Liver Diseases, Mount Sinai School of Medicine, New York, New York

Submitted 27 March 2006 ; accepted in final form 5 August 2006

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 red-stained 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 CCl₄+GA-treated animals, compared with 0.38 ± 0.07% in naive mice. -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 CCl₄-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.

cirrhosis; stellate cell; immune modulation; lymphocytes; liver injury

This article has been cited by other articles:

				R. Safadi, E. Zigmond, O. Pappo, Z. Shalev, and Y. Ilan Amelioration of hepatic fibrosis via beta-glucosylceramide-mediated immune modulation is associated with altered CD8 and NKT lymphocyte distribution Int. Immunol., August 13, 2007; (2007) dxm069v1. [Abstract] [Full Text] [PDF]