Hepatitis C virus-specific T-cell-derived transforming growth factor beta is associated with slow hepatic fibrogenesis.
Hepatitis C virus-specific T-cell-derived transforming growth factor beta is associated with slow hepatic fibrogenesis.
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DOI：
10.1002/hep.25951
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发表时间：
2012-12
期刊：
影响因子：
13.5
通讯作者：
Alatrakchi, Nadia
中科院分区：
文献类型：
--
作者：
Li, Shaoyong;Vriend, Lianne E. M.;Nasser, Imad A.;Popov, Yury;Afdhal, Nezam H.;Koziel, Margaret J.;Schuppan, Detlef;Exley, Mark A.;Alatrakchi, Nadia
丙型肝炎病毒（HCV）特异性免疫效应反应可导致慢性感染的肝损伤。肝星状细胞（HSC）是肝纤维化的主要效应细胞。我们先前鉴定了由HCV特异性CD 8 + T细胞产生的TGFβ作为调节HCV特异性效应T细胞的关键调节细胞因子。在此，我们研究了TGFβ以及HCV特异性肝内淋巴细胞（IHL）和外周血细胞在肝脏炎症和纤维化中产生的其他因子。对2组明确定义的HCV感染受试者进行的横断面研究，这些受试者具有缓慢（≤0.1 Metavir单位/年，n=13）或快速（n=6）肝纤维化进展。使用阻断调节性细胞因子的IFNγ-ELISpot ± mAb，沿着多重、ELISA和多参数FACS研究HCV特异性T细胞应答。测定用HCV核心肽刺激的IHL对促纤维化和纤维溶解基因的HSC表达的影响。阻断调节性细胞因子仅在缓慢纤维化进展者中显著提高HCV特异性效应物（IFNγ）应答的检测，在外周（p=0.003）和肝脏（p=0.01）中均如此。调节性细胞因子阻断显示HCV特异性IFNγ应答与阻断前测量的HCV特异性TGFβ强烈相关（R=0.84，p=0.0003），仅与HCV特异性IL-10相关。HCV特异性TGFβ由CD 8和CD 4 T细胞产生。HCV特异性TGFβ，而不是IL-10，与肝脏炎症呈负相关（R=-0.63，p=0.008），出乎意料的是，与纤维化呈负相关（R=-0.46，p=0.05）。此外，慢进展者HCV刺激的IHL上清液特异性增加HSC中的纤维溶解基因表达，抗TGF β mAb治疗消除了这种表达。虽然TGFβ被认为是一种主要的促纤维化细胞因子，但HCV特异性T细胞局部产生的TGFβ似乎与其他T细胞衍生因子一起在HCV感染的肝脏中具有保护作用，从而改善HCV肝病进展。
Hepatitis C virus (HCV)-specific immune effector responses can cause liver damage in chronic infection. Hepatic stellate cells (HSC) are main effectors of liver fibrosis. We previously identified TGFβ, produced by HCV-specific CD8+ T cells, as key regulatory cytokine modulating HCV-specific effector T cells. Here we studied TGFβ as well as other factors produced by HCV-specific intrahepatic lymphocytes (IHL) and peripheral blood cells in hepatic inflammation and fibrogenesis. Cross-sectional study of 2 well-defined groups of HCV-infected subjects with slow (≤0.1 Metavir units/year, n=13) or rapid (n=6) liver fibrosis progression. HCV-specific T cell responses were studied using IFNγ-ELISpot ±mAbs blocking regulatory cytokines, along with multiplex, ELISA and multi-parameter FACS. Effects of IHL stimulated with HCV-core peptides on HSC expression of pro-fibrotic and fibrolytic genes were determined. Blocking regulatory cytokines significantly raised detection of HCV-specific effector (IFNγ) responses only in slow fibrosis progressors, both in the periphery (p=0.003) and liver (p=0.01). Regulatory cytokine blockade revealed HCV-specific IFNγ responses strongly correlated with HCV-specific TGFβ, measured before blockade (R=0.84, p=0.0003), with only trend to correlation with HCV-specific IL-10. HCV-specific TGFβ was produced by CD8 and CD4 T cells. HCV-specific TGFβ, not IL-10, inversely correlated with liver inflammation (R=-0.63, p=0.008) and, unexpectedly, fibrosis (R=-0.46, p=0.05). In addition, supernatants from HCV-stimulated IHL of slow progressors specifically increased fibrolytic gene expression in HSC and treatment with anti-TGFβ mAb abrogated such expression. Although TGFβ is considered a major profibrogenic cytokine, local production of TGFβ by HCV-specific T cells appeared to have a protective role in HCV-infected liver, together with other T-cell derived factors, ameliorating HCV liver disease progression.
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影响因子：
15.9
作者：
Missale, G;Bertoni, R;Ferrari, C
通讯作者：
Ferrari, C
影响因子：
20.3
作者：
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DOI：
10.1111/j.1365-2362.2010.02381.x
发表时间：
2011-01-01
影响因子：
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作者：
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影响因子：
13.5
作者：
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通讯作者：
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影响因子：
13.5
作者：
Abel, Michal;Sene, Damien;Caillat-Zucman, Sophie
通讯作者：
Caillat-Zucman, Sophie