Werner Jens M, Serti Elisavet, Chepa-Lotrea Xenia, Stoltzfus Jonathan, Ahlenstiel Golo, Noureddin Mazen, Feld Jordan J, Liang T Jake, Rotman Yaron, Rehermann Barbara
Immunology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD.
Hepatology. 2014 Oct;60(4):1160-9. doi: 10.1002/hep.27092. Epub 2014 Aug 13.
Ribavirin (RBV) is an important component of interferon (IFN)-based and direct antiviral treatment regimens for hepatitis C virus (HCV) infection. Immunomodulation, in particular improvement of the host IFN response, has been proposed as RBV's mechanism of action. Natural killer (NK) cells are sensitive biomarkers for IFN-α/β receptor signaling, as NK cell cytotoxicity and IFN-γ production are regulated by signal transducer and activator of transcription (STAT)1- and STAT4-phosphorylation, respectively. Specifically, pSTAT1-dependent NK cell cytotoxicity increases and pSTAT4-dependent IFN-γ production decreases in response to endogenous, virus-induced IFN-α and during IFN-α-based therapy. To assess whether RBV has a direct effect on NK cells and/or improves the IFN-γ response of NK cells in the presence of IFN-α, we prospectively studied 22 HCV patients with and 32 patients without 4 weeks of RBV pretreatment, who all received subsequent pegylated (Peg)IFN/ribavirin combination therapy. During RBV pretreatment, both the frequency of CD56(dim) NK cells with cytotoxic effector functions and the frequency of CD56(bright) NK cells with the capacity to produce IFN-γ decreased (P = 0.049 and P = 0.001, respectively). In vitro or in vivo exposure of NK cells to RBV improved the pSTAT4 (P < 0.01) but not pSTAT1 response of NK cells to subsequent stimulation with IFN-α. This was associated with an increase in IFN-γ production but not cytotoxicity of NK cells during subsequent IFN-α-based therapy. The frequency of IFN-γ-producing NK cells was greater in fast second-phase virological responders than in slow responders.
RBV enhances the pSTAT4 and IFN-γ response of NK cells to IFN-α-stimulation.
利巴韦林（RBV）是基于干扰素（IFN）和直接抗病毒治疗方案治疗丙型肝炎病毒（HCV）感染的重要组成部分。免疫调节，特别是宿主IFN反应的改善，已被认为是RBV的作用机制。自然杀伤（NK）细胞是IFN-α/β受体信号传导的敏感生物标志物，因为NK细胞的细胞毒性和IFN-γ产生分别受信号转导和转录激活因子（STAT）1和STAT4磷酸化的调节。具体而言，在对内源性病毒诱导的IFN-α反应以及基于IFN-α的治疗期间，pSTAT1依赖性NK细胞毒性增加，而pSTAT4依赖性IFN-γ产生减少。为了评估RBV是否对NK细胞有直接作用和/或在存在IFN-α的情况下改善NK细胞的IFN-γ反应，我们前瞻性地研究了22例接受4周RBV预处理的HCV患者和32例未接受RBV预处理的患者，所有患者随后均接受聚乙二醇化（Peg）IFN/利巴韦林联合治疗。在RBV预处理期间，具有细胞毒性效应功能的CD56（dim）NK细胞频率和具有产生IFN-γ能力的CD56（bright）NK细胞频率均降低（分别为P = 0.049和P = 0.001）。NK细胞在体外或体内暴露于RBV后，改善了NK细胞对随后IFN-α刺激的pSTAT4反应（P <0.01），但未改善pSTAT1反应。这与随后基于IFN-α的治疗期间NK细胞的IFN-γ产生增加但细胞毒性未增加有关。快速第二阶段病毒学应答者中产生IFN-γ的NK细胞频率高于缓慢应答者。
RBV增强了NK细胞对IFN-α刺激的pSTAT4和IFN-γ反应。
