Successful Interferon-Free Therapy of Chronic Hepatitis C Virus Infection Normalizes Natural Killer Cell Function.
Successful Interferon-Free Therapy of Chronic Hepatitis C Virus Infection Normalizes Natural Killer Cell Function.
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DOI：
10.1053/j.gastro.2015.03.004
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发表时间：
2015-07
期刊：
影响因子：
29.4
通讯作者：
Rehermann B
中科院分区：
文献类型：
--
作者：
Serti E;Chepa-Lotrea X;Kim YJ;Keane M;Fryzek N;Liang TJ;Ghany M;Rehermann B
慢性丙型肝炎病毒感染激活肝内免疫应答，导致干扰素（IFN）刺激基因表达增加和自然杀伤（NK）细胞（肝脏中最普遍的先天免疫细胞）活化。我们研究了用直接作用的抗病毒药物消除丙型肝炎病毒是否能使干扰素刺激基因的表达和NK细胞功能正常化。我们使用流式细胞仪分析了13例对聚乙二醇干扰素和利巴韦林治疗无效的HCV感染患者的肝脏和血液中的NK细胞。在用达卡他韦和asunaprevir疗法进行无IFN治疗之前和期间收集样品，并与来自13名健康个体（对照）的血液的样品进行比较。ELISA法检测血清CXCL10和CXCL11水平。治疗前，所有患者的CXCL10或CXCL11水平均升高，NK细胞表型与对照组不同，其特征为HLA-DR、NKp46、NKG2A、CD85 j、pSTAT1、STAT1和TNF相关凋亡诱导配体（TRAIL）表达升高。与对照组NK细胞相比，患者NK细胞脱颗粒增加，IFN γ和TNF α产生减少。9名患者在治疗结束时出现应答（未检测到病毒），4名患者在治疗第4周至第12周之间出现病毒学突破。所有患者的病毒血症和炎性细胞因子水平的快速降低与肝内和血液NK细胞活化降低相关;随后在检测不到病毒血症的患者中，到第8周恢复正常的NK细胞表型和功能。该标准化NK细胞表型维持至第24周（EOT）。DAA介导的HCV清除与IFN α导致的肝内免疫激活丧失相关，表现为CXCL10和CXCL11水平降低以及NK细胞表型和功能正常化。
Chronic hepatitis C virus infection activates an intrahepatic immune response, leading to increased expression of interferon (IFN)-stimulated genes and activation of natural killer (NK) cells—the most prevalent innate immune cell in the liver. We investigated whether the elimination of HCV with direct-acting antiviral agents normalizes expression of IFN-stimulated genes and NK cell function. We used multicolor flow cytometry to analyze NK cells from liver and blood of 13 HCV-infected patients who did not respond to treatment with pegylated interferon and ribavirin. Samples were collected before and during IFN-free treatment with daclatasvir and asunaprevir therapy and compared with those from blood of 13 healthy individuals (controls). Serum levels of CXCL10 and CXCL11 were measured by ELISA. Before treatment, all patients had increased levels of CXCL10 or CXCL11 and a different NK cell phenotype from controls, characterized by increased expression of HLA-DR, NKp46, NKG2A, CD85j, pSTAT1, STAT1, and TNF-related apoptosis-inducing ligand (TRAIL). NK cells from patients also had increased degranulation and decreased production of IFNγ and TNFα compared with NK cells from controls. Nine patients had an end-of-treatment response (undetectable virus) and 4 had virologic breakthrough between weeks 4 and 12 of therapy. A rapid decrease in viremia and level of inflammatory cytokines in all patients was associated with decreased activation of intrahepatic and blood NK cells; it was followed by restoration of a normal NK cell phenotype and function by week 8 in patients with undetectable viremia. This normalized NK cell phenotype was maintained until week 24 (EOT). DAA-mediated clearance of HCV is associated with loss of intrahepatic immune activation by IFNα, indicated by decreased levels of CXCL10 and CXCL11 and normalization of NK cell phenotype and function.