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Role of Kupffer Cell and NK Cell Interactions in Hepatitis C Virus Infektion

库普弗细胞和 NK 细胞相互作用在丙型肝炎病毒感染中的作用

基本信息

批准号：
281237536
负责人：
Privatdozent Dr. Jens Martin Werner
金额：
--
依托单位：
Klinik und Poliklinik für Chirurgie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2015
资助国家：
德国
起止时间：
2014-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/281237536?language=en
关键词：
Role Kupffer Cell NK Interactions

项目摘要

The pathogenesis of Hepatitis C Virus (HCV)-induced liver cirrhosis is thought to be driven by the host immune system itself. KCs represent the resident macrophage population in the liver and it has been shown that they are activated and increased in frequency in the liver of chronic HCV-infected patients. Furthermore, in response to HCV, Kupffer cells (KCs) release IL-1b and IL-18 in vitro. However, a direct effect of HCV-exposed KCs on HCV replication is still unknown and the interaction between KCs and liver-infiltrating Natural Killer (NK) cells in response to HCV-replication is not studied in detail yet. This is surprising, since NK cells represent a major effector cell population involved in innate immune responses to viral infections and a Toll-like receptor (TLR)-dependent crosstalk with KCs has been described. In patients with chronic HCV infection the frequency of intrahepatic NK cells is higher and they are more activated compared to those in the peripheral blood. They display a functional dichotomy characterized by reduced production of IFNg and enhanced cytotoxicity, probably contributing to the liver injury as NK cell cytotoxicity correlates to ALT levels. Furthermore, we were recently able to link inflammasome-mediated IL-18 secretion by peripheral blood monocytes with NK cell derived IFNg production. A limitation of many previous studies is the use of mononuclear cell populations only from the blood. Indeed, it has been shown that composition and function of mononuclear cells differs between blood and liver. Therefore, the true interaction between liver mononuclear cells can only be determined through testing of cells derived from liver tissue. Taking advantage of hepatobiliary transplant surgery being performed in our department, this project is proposing to study innate immune cells in the context of HCV replication specifically in the liver, the biological more relevant compartment. In a first step, we are going to analyze the interplay of liver resident KCs and intrahepatic NK cells in response to HCV by using the HCV replicon system. We will address the question if KCs exert a direct antiviral effect and whether they also have an indirect antiviral effect via NK cell-derived IFNg production. In a second part, we will confirm our observation by using liver tissue from chronic HCV-infected patients. We will establish whether KCs from patients with chronic HCV infection have reduced TNFa-mediated (direct) and NK-cell mediated (indirect) antiviral effects and if the functional impairment of intrahepatic NK cells is reversible by using KCs from healthy controls. Finally, by following HCV+ patients prospectively during a course of HCV treatment with IFN-free direct-acting antivirals (DAAs), we will study the effect of a complete removal of the virus on peripheral innate immune cells comparing pre and post OLT patients.

丙型肝炎病毒（HCV）诱导的肝硬化的发病机制被认为是由宿主免疫系统本身驱动的。KC代表肝脏中的常驻巨噬细胞群体，并且已经显示它们在慢性HCV感染患者的肝脏中被激活并且频率增加。此外，在体外，Kupffer细胞（KCs）响应于HCV而释放IL-1b和IL-18。然而，暴露于HCV的KC对HCV复制的直接影响仍然未知，并且KC与肝脏浸润的自然杀伤（NK）细胞之间响应于HCV复制的相互作用尚未详细研究。这是令人惊讶的，因为NK细胞代表参与对病毒感染的先天免疫应答的主要效应细胞群体，并且已经描述了与KC的Toll样受体（TLR）依赖性串扰。在慢性HCV感染的患者中，肝内NK细胞的频率更高，并且与外周血中的NK细胞相比，它们更活化。它们表现出功能性二分法，其特征在于IFNg的产生减少和细胞毒性增强，可能导致肝损伤，因为NK细胞细胞毒性与ALT水平相关。此外，我们最近能够将外周血单核细胞炎症体介导的IL-18分泌与NK细胞衍生的IFNg产生联系起来。许多先前研究的局限性是仅使用来自血液的单核细胞群体。事实上，已经表明单核细胞的组成和功能在血液和肝脏之间不同。因此，肝单核细胞之间的真正相互作用只能通过检测肝组织来源的细胞来确定。利用肝胆移植手术正在我们部门进行的优势，该项目提出研究先天免疫细胞的背景下，丙型肝炎病毒的复制，特别是在肝脏，生物更相关的隔室。在第一步中，我们将通过使用HCV复制子系统来分析肝脏驻留KCs和肝内NK细胞对HCV的反应的相互作用。我们将解决的问题，如果KC发挥直接的抗病毒作用，以及他们是否也有一个间接的抗病毒作用，通过NK细胞衍生IFNg的生产。在第二部分中，我们将通过使用慢性HCV感染患者的肝组织来证实我们的观察结果。我们将确定慢性HCV感染患者的KCs是否降低了TNF α介导的（直接）和NK细胞介导的（间接）抗病毒作用，以及使用健康对照组的KCs是否可以逆转肝内NK细胞的功能损伤。最后，通过前瞻性地随访HCV+患者，在用无IFN的直接作用抗病毒药物（DAA）治疗HCV的过程中，我们将研究完全清除病毒对外周先天免疫细胞的影响，比较奥尔特前后患者。