Regulation of dendritic cell function and cell-based therapy in chronic hepatitis C virus infection

慢性丙型肝炎病毒感染中树突状细胞功能的调节和细胞治疗

• 批准号: 15109006
• 负责人: HAYASHI Norio
• 金额: $ 72.13万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (S)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15109006/
• 关键词: chronic hepatitis C; hepatocellular carcinoma; dendritic cell; natural killer cell; innate immuni; NK receptor; Toll-like receptor; RIG-I; RIG-I; インターフェロン; regulatory T細胞; ペグインターフェロン; リバビリン; 持続ALT正常; FoxP3; IL-10; Th1; 免疫; blood DC; 先天免

Sequential activation of innate and adaptive immune response is crucial for virus elimination. Dendritic cells (DCs) sense virus infection via toll-like receptors (TLR) or retinoic acid inducible gene-I (RIG-I), resulting in the secretion of type-I interferons (IFN) and inflammatory cytokines. Blood DC consist of two subsets; myeloid DC (MDC) and plasmacytoid DC (PDC). In chronic hepatitis C patients, both of these DC subsets decreased compared to healthy subjects. Furthermore, MDC and PDC are functionally impaired in HCV-infected patients in the ability to stimulate T cell proliferation as well as cytokine secretion. In MDC from HCV-infected patients, regardless of higher expression of TLR2, TLR4 and RIG-I compared to the controls, the levels of TLR/RIG-I-mediated IFN-β, TNF-α or IL-12p70 induction are lower than those in uninfected donors. These results suggest that the signal transduction in the downstream of TLR/RIG-I in DC is profoundly impaired in HCV infection. In order to searc … More h for the mechanisms of above-mentioned DC malfunction in HCV infection, we inoculated pseudo-HCV particles, covered by chimeric HCV E1/E2 protein, to MDC or PDC recovered from healthy donors. Pseudo-HCV enters only MDC but not PDC, suggesting that HCV aims to infect myeloid subsets. However, unanswered question still remains for the mechanisms of HCV-induced PDC dysfunction. Cumulative reports have been published for pervasive impairment in adaptive immune system in HCV infection, such as virus-specific CD4^+ or CD8^+ T cells. Naturally occurring regulatory T cells (Tregs) are specialized T cell subsets that are capable of suppressing auto-reactive T cells. In order to clarify the roles of Treg in chronic HCV infection, we compared the frequency and function of Tregs between the patients and uninfected donors. Peripheral Tregs in chronic HCV infection is greater in frequency and in suppressive ability than those in healthy counterparts, much more in patients with persistently normal ALT levels compared to those with active hepatitis. These results imply that the abundance of Treg is beneficial for the maintenance of low-grade liver inflammation, possibly by suppressing inflammatory Th1 cells. In conclusion, active and reciprocal interactions among innate and adaptive immune cells, which are orchestrated by DC, are critical in shaping immuno-pathogenesis of HCV infection. Less

先天性和适应性免疫反应的顺序激活对于病毒消除至关重要，树突状细胞 (DC) 通过 Toll 样受体 (TLR) 或视黄酸诱导基因-I (RIG-I) 感知病毒感染，从而分泌 1 型病毒。 I 干扰素 (IFN) 和炎症细胞因子由两个亚型组成：髓样 DC (MDC) 和浆细胞样 DC (PDC)。此外，与健康受试者相比，HCV 感染患者的 MDC 和 PDC 刺激 T 细胞增殖和细胞因子分泌的功能受损，无论 TLR2 的表达是否较高。 TLR4和RIG-I与对照相比，TLR/RIG-I介导的IFN-β、TNF-α或IL-12p70诱导水平低于未感染供体中的水平。这些结果表明，HCV感染时DC中TLR/RIG-I下游的信号转导受到严重损害。为了探究HCV感染中上述DC故障的机制，我们接种了假HCV。被嵌合HCV E1/E2蛋白覆盖的颗粒，从健康供体中回收的MDC或PDC，伪HCV仅进入MDC，但不进入PDC，这表明HCV旨在感染骨髓。然而，HCV 诱导的 PDC 功能障碍的机制仍然存在悬而未决的问题。关于 HCV 感染中适应性免疫系统（例如病毒特异性 CD4^+ 或 CD8^+ T 细胞）普遍受损的累积报告。调节性 T 细胞 (Treg) 是一种特殊的 T 细胞亚群，能够抑制自身反应性 T 细胞。为了阐明 Treg 在慢性 HCV 感染中的作用，我们比较了 Treg 的频率和功能。慢性 HCV 感染患者和未感染的供体中的外周 Treg 的频率和抑制能力均高于健康盟友，并且与活动性肝炎患者相比，ALT 水平持续正常的患者中的外周 Treg 的丰度更高。可能通过抑制炎症性 Th1 细胞，有利于维持低度肝脏炎症。 总之，由 DC 精心策划的先天性免疫细胞和适应性免疫细胞之间的主动相互作用对于形成免疫发病机制至关重要。 HCV 感染较少。

项目成果

Dendritic cells and regulatory T cells as decision markers for the duration of pegylated interferon-α and ribavirin therapy in chronic hepatitis C patients.

树突状细胞和调节性 T 细胞作为慢性丙型肝炎患者聚乙二醇化干扰素-α 和利巴韦林治疗持续时间的决策标记。

• 发表时间: 2007
• 作者: Kanto T; Itose I; et. al.
• 通讯作者: et. al.

Jinushi M, Takehara T, et al.: "Autocrine/paracrine IL-15 that is required for type I IFN-mediated dendritic cell expression of MHC class I-related chain A and B is impaired in hepatitis C virus infection"Journal of Immunology. 171(10). 5423-5429 (2003)

Jinushi M、Takehara T 等人：“I 型 IFN 介导的 MHC I 类相关链 A 和 B 的树突状细胞表达所需的自分泌/旁分泌 IL-15 在丙型肝炎病毒感染中受损”免疫学杂志

Critical Role of MHC Class I-Related Chain A and B Expression on IFN-α-Stimulated Dendritic Cells in NK Cell Activation: Impairment in Chronic Hepatitis C Virus Infection 1

MHC I 类相关链 A 和 B 表达对 IFN-α 刺激的树突状细胞在 NK 细胞激活中的关键作用：慢性丙型肝炎病毒感染的损伤 1

• DOI: 10.4049/jimmunol.170.3.1249
• 发表时间: 2003-02-01
• 期刊: The Journal of Immunology
• 作者: M. Jinushi;T. Takehara;T. Kanto;T. Tatsumi;V. Groh;T. Spies;T. Miyagi;Takahiro Suzuki;Y. Sasaki
• 通讯作者: Y. Sasaki

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
• 作者: Oze T; Hayashi N; et al.
• 通讯作者: et al.

Quick generation of fully mature dendritic cells from monocytes with OK432, low-doseprostanoid and interferon-α 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
• 作者: Sakakibara M; Takehara T; et al.
• 通讯作者: et al.