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

基于浆细胞样树突状细胞的病毒性肝炎和肝细胞癌免疫疗法的建立

• 批准号: 16590592
• 负责人: KANTO Tatsuya
• 金额: $ 2.56万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590592/
• 关键词: Chronic hepatitis C; Dendritic cells; Toll-like receptor; Pegylated interferon-a; Ribavirin; Regulatory T cells; RIG-I; Th1; Th2; インターフェロンα

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

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）的发病机制中的作用。此外，我们旨在阐明DC系统在基于ifn的抗hcv治疗疗效中的作用。与健康献血者相比，hcv感染患者血液中MDC和PDC的频率降低。两个DC亚群的能力，如细胞因子的产生和T细胞和NK细胞的刺激，也明显受损。在Thl极化能力方面，患者的MDC诱导Thl反应的能力较弱。然而，来自患者的PDC诱导了更多产生il -10的调节性T细胞，有助于减轻肝脏炎症：在接受48周peg-IFNα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。在获得持续病毒学应答（SVR）的患者中，治疗过程中PDC频率更高，治疗结束时DC能力优于出现短暂应答（TR）的患者。这些结果表明，PDC频率和DC功能的维持与ifn介导的HCV根除有关。树突状细胞利用toll样受体（TLR）、RIG-I和MDA-5感知病毒并诱导先天和适应性免疫反应。TLR2、TLR4和rig - 1在MDC患者中的表达明显高于供体MDC。相比之下，TLR3和MDA-5的表达在两组之间具有可比性。当使用针对TLR2、TLR3、TLR4和RIG-I的特异性激动剂刺激时，来自患者的MDC诱导的IFN-β和TNF-α显著减少，这表明患者MDC中TLR和RIG-I下游的信号转导受损。综合RT-PCR分析，患者MDC中TRIF和TRAF6表达水平显著降低，提示其可能在hcv诱导的信号干扰中起作用。综上所述，DC系统是抗HCV免疫治疗的关键靶点：增强MDC功能可根除HCV，增强PDC功能可延缓疾病进展。少

项目成果

Reduced expression and functional impairment of Toll-like receptor 2 on dendritic cells in chronic hepatitis C virus infection.

• DOI: 10.1016/j.hepres.2005.12.010
• 发表时间: 2006-03
• 期刊: Hepatology research : the official journal of the Japan Society of Hepatology
• 作者: T. Yakushijin;T. Kanto;M. Inoue;T. Oze;M. Miyazaki;Ichiyo Itose;H. Miyatake;Mitsuru Sakakibara;N. Kuzushita;N. Hiramatsu;T. Takehara;A. Kasahara;N. Hayashi

Hepatocyte-specific disruption of Bcl-xL leads to continuous hepatocyte apoptosis and liver fibrotic responses

• DOI: 10.1053/j.gastro.2004.07.019
• 发表时间: 2004-10-01
• 期刊: GASTROENTEROLOGY
• 影响因子: 29.4
• 作者: Takehara, T;Tatsumi, T;Hayashi, N
• 通讯作者: Hayashi, N

Impaired ability of interferon-alpha-primed dendritic cells to stimulate Th1-type CD4 T-cell response in chronic hepatitis C virus infection

• DOI: 10.1111/j.1365-2893.2006.00814.x
• 发表时间: 2007-06-01
• 期刊: JOURNAL OF VIRAL HEPATITIS
• 影响因子: 2.5
• 作者: Miyatake, H.;Kanto, T.;Hayashi, N.
• 通讯作者: Hayashi, N.

Impaired ability of interferon-alpha-primed dendritic cells to stimulate Thl-type CD4 T cell response in chronic hepatitis C virus infection.

在慢性丙型肝炎病毒感染中，干扰素α引发的树突状细胞刺激Thl型CD4 T细胞反应的能力受损。

• 发表时间: 2007
• 期刊: J Viral Hepatitis (in press)
• 作者: Miyatake;H.;Kanto;T.;et al.
• 通讯作者: et al.

Early decline of hemoglobin correlates with progression of ribavirin-induced hemolytic anemia during interferon plus ribavirin combination therapy in patients with chronic hepatitis C.

慢性丙型肝炎患者在干扰素加利巴韦林联合治疗期间，血红蛋白的早期下降与利巴韦林诱导的溶血性贫血的进展相关。

• 发表时间: 2006
• 期刊: J Gastroenterol 41・9
• 作者: Uno S;et al.;Wada A;Ujiie H;Matsumoto H;Fukui K;Oze T
• 通讯作者: Oze T