Impact of alpha interferon and ribavirin on the function of maturing dendritic cells
Impact of alpha interferon and ribavirin on the function of maturing dendritic cells
复制标题
DOI：
10.1128/aac.48.9.3382-3389.2004
复制
发表时间：
2004-09-01
影响因子：
4.9
通讯作者：
Klenerman, P
中科院分区：
文献类型：
--
作者：
Barnes, E;Salio, M;Klenerman, P
在丙型肝炎病毒（HCV）感染的治疗中，α干扰素和利巴韦林需要联合使用以获得持续的病毒学应答。α干扰素具有直接的抗病毒活性，也能增强HCV特异性T细胞应答。利巴韦林对HCV几乎没有直接活性，但可减轻肝脏炎症。因此，这些药物组合可能具有迄今为止尚未确定的免疫学效应。在本研究中，我们研究了α干扰素和利巴韦林对体外双链RNA诱导的树突状细胞（DC）成熟和细胞因子产生的影响。α干扰素单独增强了未成熟DC上HLA I类、HLA II类和CD 86的表达，但不刺激完全DC成熟，这需要CD 83的表达。α干扰素增强白细胞介素12 p70 [IL-12（p70）]和肿瘤坏死因子α（TNF-α）的产生，但对IL-10的产生没有影响。相反，生理剂量的利巴韦林对DC成熟没有影响，但显著抑制TNF-α、IL-10和IL-12（p70）的产生。利巴韦林对细胞因子的抑制不能通过诱导DC凋亡或细胞死亡来解释。定量PCR证实细胞因子抑制发生在mRNA水平。IL-12（p70）和TNF-α在成熟DC中的抑制可以解释在利巴韦林单药治疗期间观察到的肝脏炎症的减少。α干扰素-利巴韦林联合治疗可通过抑制IL-10的产生但维持IL-12（p70）和TNF-α的产生来改变成熟DC的总体细胞因子谱，这种模式有利于通过对T细胞的下游作用消除病毒。
Alpha interferon and ribavirin are required in combination to achieve a sustained virological response in the treatment of hepatitis C virus (HCV) infection. Alpha interferon has direct antiviral activity and also enhances HCV-specific T-cell responses. Ribavirin has little direct activity against HCV but reduces hepatic inflammation. It is therefore likely that these drugs in combination have hitherto unidentified immunological effects. In the present study we investigated the effects of alpha interferon and ribavirin on dendritic cell (DC) maturation and cytokine production induced by double-stranded RNA in vitro. Alpha interferon alone enhanced the expression of HLA class I, HLA class II, and CD86 on immature DCs but did not stimulate full DC maturation, which requires the expression of CD83. Alpha interferon enhanced the production of interleukin 12 p70 [IL-12(p70)] and tumor necrosis factor alpha (TNF-alpha) but had no effect on IL-10 production. In contrast, ribavirin at physiological doses had no effect on DC maturation but markedly suppressed the production of TNF-alpha, IL-10, and IL-12(p70). The suppression of cytokines by ribavirin cannot be explained by the induction of DC apoptosis or cell death. Quantitative PCR confirmed that cytokine suppression occurs at the level of mRNA. The suppression of IL-12(p70) and TNF-alpha in maturing DCs may explain the reduction in hepatic inflammation observed during ribavirin monotherapy. Combination alpha interferon-ribavirin therapy may alter the cytokine profile of maturing DCs overall by suppressing IL-10 production but maintaining IL-12(p70) and TNF-alpha production, a pattern that would favor viral elimination through downstream effects on T cells.