Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA 02215, USA.
Hepatology. 2012 Dec;56(6):2094-105. doi: 10.1002/hep.25951.
Hepatitis C virus (HCV)-specific immune effector responses can cause liver damage in chronic infection. Hepatic stellate cells (HSC) are the main effectors of liver fibrosis. TGFβ, produced by HCV-specific CD8(+) T cells, is a 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. This was a cross-sectional study of two 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 interferon-gamma (IFNγ)-ELISpot ±monoclonal antibodies (mAbs) blocking regulatory cytokines, along with multiplex, enzyme-linked immunosorbent assay (ELISA) and multiparameter fluorescence-activated cell sorting (FACS). The effects of IHL stimulated with HCV-core peptides on HSC expression of profibrotic 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 a trend to correlation with HCV-specific IL-10. HCV-specific TGFβ was produced by CD8 and CD4 T cells. HCV-specific TGFβ, not interleukin (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.
丙型肝炎病毒（HCV）特异性免疫效应反应可导致慢性感染中的肝损伤。肝星状细胞（HSC）是肝纤维化的主要效应细胞。HCV 特异性 CD8+T 细胞产生的 TGFβ是调节 HCV 特异性效应 T 细胞的关键调节细胞因子。在这里，我们研究了 TGFβ以及由 HCV 特异性肝内淋巴细胞（IHL）和外周血细胞产生的其他因子在肝炎症和纤维化中的作用。这是一项对两组明确的 HCV 感染患者的横断面研究，其纤维化进展速度较慢（≤0.1 Metavir 单位/年，n=13）或较快（n=6）。使用干扰素-γ（IFNγ）-ELISpot±单克隆抗体（mAb）阻断调节细胞因子，以及多重、酶联免疫吸附测定（ELISA）和多参数荧光激活细胞分选（FACS）研究了 HCV 特异性 T 细胞反应。测定了用 HCV 核心肽刺激的 IHL 对 HSC 表达纤维生成和纤维溶解基因的影响。仅在纤维化进展较慢的患者中，阻断调节细胞因子可显著提高 HCV 特异性效应（IFNγ）反应的检测率，无论是在外周（P=0.003）还是在肝脏（P=0.01）。调节细胞因子阻断揭示 HCV 特异性 IFNγ 反应与 HCV 特异性 TGFβ强烈相关，在阻断之前进行测量（R=0.84，P=0.0003），仅呈与 HCV 特异性 IL-10 相关的趋势。HCV 特异性 TGFβ由 CD8 和 CD4 T 细胞产生。HCV 特异性 TGFβ，而非白细胞介素（IL）-10，与肝炎症（R=-0.63，P=0.008），出人意料地与纤维化（R=-0.46，P=0.05）呈负相关。此外，来自纤维化进展较慢的患者的 HCV 刺激的 IHL 的上清液特异性增加了 HSC 的纤维溶解基因表达，并且用抗 TGFβ mAb 治疗消除了这种表达。
尽管 TGFβ被认为是主要的促纤维化细胞因子，但 HCV 特异性 T 细胞的局部产生似乎在 HCV 感染的肝脏中具有保护作用，与其他 T 细胞衍生的因子一起，改善 HCV 肝病的进展。
