Miyatake H, Kanto T, Inoue M, Sakakibara M, Kaimori A, Yakushijin T, Itose I, Miyazaki M, Kuzushita N, Hiramatsu N, Takehara T, Kasahara A, Hayashi N
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita-shi, Osaka, Japan.
J Viral Hepat. 2007 Jun;14(6):404-12. doi: 10.1111/j.1365-2893.2006.00814.x.
In interferon-alpha (IFN-alpha)/ribavirin combination therapy for chronic hepatitis C (CHC), an enhanced T helper 1 (Th1) response is essential for the eradication of hepatitis C virus (HCV). We aimed to elucidate the role of IFN-alpha or IFN-alpha/ribavirin in dendritic cell (DC) ability to induce Th1 response in HCV infection. We generated monocyte-derived DC from 20 CHC patients and 15 normal subjects driven by granulocyte-macrophage colony-stimulating factor and interleukin 4 (IL-4) without IFN-alpha (GM/4-DC), with IFN-alpha (IFN-DC), with ribavirin (R-DC) or with IFN-alpha/ribavirin (IFN/R-DC) and compared their phenotypes and functions between the groups. We also compared them in 14 CHC patients between who subsequently attained sustained virological response (SVR) and who did not (non-SVR) by 24 weeks of IFN-alpha/ribavirin therapy. Compared with GM/4-DC, IFN-DC displayed higher CD86 expression, but lesser ability to secrete IL-10 and were more potent to prime CD4(+) T cells to secrete IFN-gamma and IL-2. Such differences were more significant in healthy subjects than in CHC patients. No additive effect of ribavirin was observed in DC phenotypes and functions in vitro either which was used alone or in combined with IFN-alpha. However, in the SVR patients, an ability of IFN/R-DC to prime T cells to secrete IFN-gamma and IL-2 was higher than those of IFN-DC and those of IFN/R-DC in the non-SVR group, respectively. In conclusion, DC from CHC patients are impaired in the ability to drive Th1 in response to IFN-alpha. Such DC impairment is restored in vitro by the addition of ribavirin in not all but some patients who cleared HCV by the combination therapy.
在干扰素-α（IFN-α）/利巴韦林联合治疗慢性丙型肝炎（CHC）中，增强的辅助性T细胞1（Th1）反应对于清除丙型肝炎病毒（HCV）至关重要。我们旨在阐明IFN-α或IFN-α/利巴韦林在HCV感染中树突状细胞（DC）诱导Th1反应能力方面的作用。我们从20例CHC患者和15名正常受试者中分离出单核细胞来源的DC，分别在粒细胞-巨噬细胞集落刺激因子和白细胞介素4（IL-4）驱动下，不添加IFN-α（GM/4-DC）、添加IFN-α（IFN-DC）、添加利巴韦林（R-DC）或添加IFN-α/利巴韦林（IFN/R-DC），并比较了各组之间的表型和功能。我们还比较了14例CHC患者在接受IFN-α/利巴韦林治疗24周后获得持续病毒学应答（SVR）和未获得（非SVR）患者之间的差异。与GM/4-DC相比，IFN-DC表现出更高的CD86表达，但分泌IL-10的能力较低，并且在激活CD4(+)T细胞分泌IFN-γ和IL-2方面更有效。这些差异在健康受试者中比在CHC患者中更显著。单独使用或与IFN-α联合使用时，利巴韦林在体外对DC的表型和功能均未观察到相加作用。然而，在SVR患者中，IFN/R-DC激活T细胞分泌IFN-γ和IL-2的能力分别高于IFN-DC和非SVR组中的IFN/R-DC。总之，CHC患者的DC在对IFN-α反应中驱动Th1的能力受损。在体外，通过添加利巴韦林，并非所有但部分通过联合治疗清除HCV的患者中这种DC损伤得以恢复。
