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Increased Th1, Th17 and pro-fibrotic responses in hepatitis C-infected patients are down-regulated after 12 weeks of treatment with pegylated interferon plus ribavirin |
European Cytokine Network. Volume 21, Number 2, 84-91, June 2010, research article
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 Free Article
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Author(s) : Maria Angeles Jimenez-Sousa, Raquel Almansa, Concha de la Fuente, Agustín Caro-Paton, Lourdes Ruiz, Gloria Sanchez-Antolín, Jose Manuel Gonzalez, Rocio Aller, Noelia Alcaide, Pilar Largo, Salvador Resino, Raul Ortiz de Lejarazu, Jesus F Bermejo-Martin |
Summary : Hepatitis C virus causes significant morbidity and mortality worldwide. The infection induces up-regulation of cytokine and chemokines commonly linked to the development of cellular and pro-inflammatory antiviral responses. The current standard in hepatitis C treatment consists of combination regimens of pegylated interferon-alpha plus ribavirin. The impact of combined treatment in the host immune response is still poorly understood. In the present study, we profiled 27 cytokines, chemokines and growth factors involved in the innate and adaptive responses to the virus in the serum of 27 hepatitis C virus-infected patients, before and after 12 weeks of combined treatment, and compared them to 10 healthy controls. Hepatitis C virus infection induced not only the secretion of chemokines and cytokines participating in Th1 responses (MIP-1α, IP-10, TNF-α, IL-12p70, IL-2), but also cytokines involved in the development of Th17 responses (IL-6, IL-8, IL-9 and IL-17) and two pro-fibrotic factors (FGF-b, VEGF). The most important increases included MIP-1α (4.7-fold increase compared to the control group), TNF-α (3.0-fold), FGF-b (3.4-fold), VEGF (3.5-fold), IP-10 (3.6-fold), IL-17 (107.0-fold), IL-9 (7.5-fold), IL-12p70 (7.0-fold), IL-2 (5.6-fold) and IL-7 (5.6-fold). Combined treatment with pegylated interferon-alpha plus ribavirin down-modulated the secretion of key Th1 and Th17 pro-inflammatory mediators, and pro-fibrotic growth factors as early as 12 weeks after treatment initiation. MIP-1α, FGF-b, IL-17 decreased in a more dramatic manner in the group of responder patients than in the group of non-responders (fold-change in cEVR\; fold-change in NcEVR): MIP-1α (4.72\;1.71), FGF-b (4.54\;1.21), IL-17 (107.1\;1.8). Correlation studies demonstrated that the decreases in the levels of these mediators were significantly associated with each other, pointing to a coordinated effect of the treatment on their secretion (r coefficient\; p value): [∆ FGF-b versus ∆ IL-17 (0.90\; 0.00), ∆ IL-17 versus ∆ VEGF (0.88\; 0.00), ∆ MIP-1α versus ∆ IL-17 (0.84\;0.00), ∆ FGF-b versus ∆ MIP-1α (0.96\;0.00), ∆ FGF-b versus ∆ IL-12p70 (0.90\; 0.00), ∆ VEGF versus ∆ IL-12p70 (0.89\; 0.00)]. Th17 immunity has been previously associated with autoimmune diseases and asthma, but this is the first work reporting a role for this profile in viral hepatitis. These results provide an opportunity to evaluate the impact of the treatment with Peg-INF-alpha and RBV on the prevention of immune-driven tissue damage in infected patients. |
Keywords : cEVR, Complete early virological response, FGF-b, Fibroblast growth factor - basic, G-CSF, Granulocyte colony-stimulating factor, GM-CSF, Granulocyte macrophage colony-stimulating factor, HCV, Hepatitis C virus, IFN-γ, Interferon γ, IP-10, Interferon-gamma inducible protein-10, MCP-1, Monocyte chemoattractant protein-1, MIP-1α, Macrophage inflammatory protein-1α, MIP-1β, Macrophage inflammatory protein-1β, NcEVR, Non-complete early virological response, Peg-INF-alpha, Pegylated interferon-alpha, PDGF, Platelet-derived growth factor, RANTES, Regulated upon activation, normal T-cell expressed, and secreted, RBV, Ribavirin, TNF-α, Tumor necrosis factor α, VEGF, Vascular endothelial growth factor |
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