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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

基本信息

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

项目摘要

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相继激活对于消除病毒至关重要。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I型干扰素（IFN）和炎症细胞因子。血液 DC 由两个子集组成；髓样 DC (MDC) 和浆细胞样 DC (PDC)。在慢性丙型肝炎患者中，与健康受试者相比，这两个 DC 亚群均有所下降。此外，HCV 感染患者的 MDC 和 PDC 刺激 T 细胞增殖和细胞因子分泌的能力受到功能损害。在 HCV 感染患者的 MDC 中，尽管与对照组相比 TLR2、TLR4 和 RIG-I 表达较高，但 TLR/RIG-I 介导的 IFN-β、TNF-α 或 IL-12p70 诱导水平低于未感染供者。这些结果表明，在HCV感染中，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，我们将嵌合HCV E1/E2蛋白覆盖的假HCV颗粒接种到从健康供体中回收的MDC或PDC中。假性HCV仅进入MDC而不进入PDC，这表明HCV旨在感染骨髓亚群。然而，HCV 引起的 PDC 功能障碍的机制仍然存在悬而未决的问题。已发表关于 HCV 感染中适应性免疫系统普遍受损的累积报告，例如病毒特异性 CD4^+ 或 CD8^+ T 细胞。天然存在的调节性 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，我们比较了患者和未感染供者之间Treg的频率和功能。慢性 HCV 感染者的外周 Tregs 的频率和抑制能力均高于健康人群，且与活动性肝炎患者相比，ALT 水平持续正常的患者的外周 Tregs 水平更高。这些结果表明，丰富的 Treg 有利于维持低度肝脏炎症，可能是通过抑制炎症 Th1 细胞来实现的。总之，由 DC 协调的先天性免疫细胞和适应性免疫细胞之间的积极和相互的相互作用对于形成 HCV 感染的免疫发病机制至关重要。较少的