Establishment of plasmacytoid dendritic cell-based immune therapy against viral hepatitis and hepatocellular carcinoma

该研究项目的目的是阐明树突状细胞（DC），包括髓样DC（MDC）或浆细胞样DC（PDC）在丙型肝炎病毒诱导的慢性肝炎和肝细胞癌（HCC）发病机制中的作用。此外，我们旨在阐明DC系统在基于IFN-α的抗HCV治疗效果中的作用。与健康供体相比，HCV感染患者的血液MDC和PDC频率降低。两种DC亚群的能力，如细胞因子产生和刺激T细胞和NK细胞的能力也显著受损。在Th极化能力方面，患者MDC诱导Th 1应答的能力较弱。然而，患者的PDC诱导更多的IL-10产生调节性T细胞，有助于减轻肝脏炎症：在接受48周聚乙二醇-IFN α和利巴韦林治疗的慢性丙型肝炎患者中，我们检查了整个治疗过程中DC亚群的频率和DC功能。 ...更多信息 持续病毒学应答（SVR）患者治疗过程中的PDC频率和治疗结束时的DC能力均高于一过性应答（TR）患者。树突状细胞通过Toll样受体（TLR）、RIG-I和MDA-5等受体感受病毒，诱导机体产生先天性和适应性免疫应答。患者MDC中TLR 2、TLR 4和RIG-I的表达明显高于供体MDC。而TLR 3和MDA-5的表达在两组间无明显差异。当用TLR 2、TLR 3、TLR 4和RIG-I的特异性激动剂刺激时，患者MDC诱导的IFN-β和TNF-α显著减少，表明患者MDC中TLR和RIG-I下游的信号转导受损。RT-PCR结果显示，患者MDC中TRIF和TRAF 6的表达水平显著降低，提示其可能参与HCV诱导的信号干扰。总之，DC系统是抗HCV免疫治疗的重要靶点：增强MDC的功能可导致HCV根除，增强PDC的功能可延缓疾病进展。少

The aim of the research project was to clarify the roles of dendritic cells (DC), including myeloid DC (MDC) or plasmacytoid DC (PDC), in the pathogenesis of hepatitis C virus-induced chronic hepatitis and hepatocellular carcinoma (HCC). In addition, we aimed to clarify the roles of DC system in the efficacy of IFN-a-based anti-HCV treatment.The frequencies of blood MDC and PDC were decreased in HCV-infected patients compared to healthy donors. The abilities of both DC subsets, such as cytokine production and stimulation of T cells and NK cells, were significantly impaired as well. With regard to the capacity of Th polarization, MDC from the patients were less able to induce Thl response. However, PDC from the patients induced more IL-10-producing regulatory T cells, contributing to the alleviation of liver inflammation:In chronic hepatitis C patients who underwent 48-week peg-IFNα and ribavirin therapy, we examined the frequencies of DC subsets and DC function throughout the therapy. … More In patients who attained sustained virological response (SVR), PDC frequency during the course was higher and DC ability at the end of therapy was better than those in patients who showed transient response (TR). These results demonstrate that maintenance of PDC frequency and DC function are involved in the IFN-mediated HCV eradication.Dendritic cells utilize toll-like receptors (TLR), RIG-I and MDA-5 to sense virus and induce innate as well as adaptive immune responses. The expressions of TLR2,TLR4 and RIG-I in patients MDC were significantly higher than those in donor MDC. In contrast, TLR3 and MDA-5 expressions were comparable between them. When stimulated with specific agonists against TLR2,TLR3,TLR4 and RIG-I, MDC from the patients induced significantly less IFN-β and TNF-α, indicating signal transduction in the downstream of TLR and RIG-I was impaired in MDC from the patients. From the comprehensive RT-PCR analyses, the levels of TRIF and TRAF6 expression were significantly decreased in patient MDC, suggesting the possible role in HCV-induced signal interference.In summary, DC system is a critical target of anti-HCV immune therapy: enhancing function of MDC leads to HCV eradication and that of PDC for retardation of disease progression, respectively. Less