背景/目的:丙型肝炎病毒特异的免疫效应反应可以引起慢性感染导致肝损伤。肝星形细胞是引起肝纤维化的主要细胞。我们之前研究过由HCV特异的CD8(+)T细胞产生的TGFβ，是调节HCV特异的效应T细胞的主要细胞因子。这里我们研究由HCV特异的肝内淋巴细胞和外周血细胞产生的TGFβ以及其他细胞因子对肝炎及肝纤维化的影响。方法:横断面研究两组HCV感染的患者，分别是较慢 (<0.1 Metavir units/year, n=13) 和较快的(n=6)肝脏纤维化进程。用IFNγ-ELISpot±封闭细胞因子mAbs，联合multiplex, ELISA 和多参数FACS 来检测HCV特异的T细胞反应。通过用HCV核心肽刺激并在肝脏的星型细胞所表达的成纤维和纤维溶解的基因来检测IHL的效应。结果:只有在肝纤维化缓慢进展的患者的外周血(p=0.003)和肝脏内(p=0.01)，封闭调节因子可以显著的增加HCV特异效应反应。阻滞调节因子显示HCV特异的IFNγ与在封闭之前与HCV特异的TGFβ相关性很大(R=0.84, p=0.0003)，并且有与HCV特异的IL10相关的趋势。HCV特异的TGFβ由CD8和CD4细胞产生。HCV特异的TGFβ，但不是IL10，与肝脏炎症和肝纤维化呈负相关。另外，由HCV刺激肝纤维化缓慢的患者肝内淋巴细胞培养所得到的上清液显示肝星型细胞表达的纤溶基因显著增加，但加入抗TGFβ单克隆抗体就可以抵消这种纤溶基因的高表达。结论：尽管TGFβ被认为是主要的促肝脏纤维化因子，但是HCV特异的T细胞所产生的TGFβ和其他的细胞因子在丙肝病毒感染的肝脏中可能起保护作用，并且可以缓解丙肝病情。

吉林大学第一医院肝胆胰内科 高修竹 摘译
本文首次发表于[Hepatology.2012 Jul 14. doi: 10.1002/hep.25951.]

　　

Hepatitis C virus-specific T cell-derived transforming growth factor beta is associated with slow hepatic fibrogenesis

BACKGROUND/AIMS:
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.
METHODS:
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.
RESULTS:
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.
CONCLUSION:
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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