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）发病机制中的作用。 ，我们的目的是阐明DC系统在以IFN-α为基础的抗HCV治疗疗效中的作用。与HCV感染者相比，HCV感染者血液中MDC和PDC的频率降低健康供体的两种 DC 亚群的能力，例如细胞因子产生以及 T 细胞和 NK 细胞的刺激能力，也显着受损。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 DC 亚群和利巴韦林治疗的频率。整个治疗过程中的 DC 功能……更多 在获得持续病毒学应答 (SVR) 的患者中，治疗过程中的 PDC 频率较高，且治疗结束时的 DC 能力优于表现出短暂应答 (TR) 的患者。证明 PDC 频率和 DC 功能的维持参与 IFN 介导的 HCV 根除。树突状细胞利用 Toll 样受体 (TLR)、RIG-I 和 MDA-5 来感知病毒并诱导先天性和适应性免疫患者MDC中TLR2、TLR4和RIG-I的表达显着高于供体MDC，相反，当用针对TLR2、TLR3、TLR4和TLR4的特异性激动剂刺激时，它们之间的TLR3和MDA-5表达相当。患者的 RIG-I、MDC 诱导的 IFN-β 和 TNF-α 显着减少，表明患者 MDC 中 TLR 和 RIG-I 下游的信号转导受损。从综合RT-PCR分析来看，MDC患者中TRIF和TRAF6表达水平显着降低，提示其可能在HCV诱导的信号干扰中发挥作用。综上所述，DC系统是抗HCV免疫治疗的关键靶点： MDC 的功能可导致 HCV 根除，PDC 的功能可延缓疾病进展。

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

Quick generation of fully mature dendritic cells from monocytes with OK432, low-dose prostanoid, and interferon-alpha as potent immune enhancers.

使用 OK432、低剂量前列腺素和干扰素-α 作为有效的免疫增强剂，从单核细胞快速生成完全成熟的树突状细胞。

• 发表时间: 2006
• 期刊: Journal of Immunotherapy 29
• 作者: Sakakibara;M.;Kanto;T.et al.
• 通讯作者: T.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

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.

Involvement of dendritic cell frequency and function in virological relapse in pegylated interferon-α2b and ribavirin therapy for chronic hepatitis C patients.

慢性丙型肝炎患者聚乙二醇干扰素-α2b 和利巴韦林治疗中树突状细胞频率和功能与病毒学复发的关系。

• 发表时间: 2007
• 期刊: Journal of Medical Virology 79
• 作者: Itose I.;Kanto T.;Inoue;M.;Miyazaki;M.;Miyatake;H.;Sakakibara;M.;Yakushijin;T.;Oze;T.;Hiramatsu;N.;Takehara;T.;Kasahara;A.;Hayashi;N.
• 通讯作者: N.