Innate-like hepatic CD1d-reactive NKT cell:Liver Disease

描述(申请人提供)：全球有近2亿人感染丙型肝炎病毒。近2%的美国人口感染了丙型肝炎病毒，在一些人口群体中，丙型肝炎病毒的水平要高得多。在大多数情况下，接触丙型肝炎病毒会导致持续的慢性感染，大多数病例在出现症状之前都没有被发现。免疫抑制，无论是由于与几种病原体的混合感染还是由于治疗，都会显著促进丙型肝炎病毒介导的疾病进展。因此，丙型肝炎病毒感染仍将是长期的主要公共卫生负担。尽管最近有证据表明，丙型肝炎病毒感染早期的免疫反应失败会导致持续感染，但对第一道防线--先天免疫--知之甚少。关于丙型肝炎病毒感染患者外周血中T细胞的相关信息很多，但对于大约25%的肝内淋巴细胞(IHL)是‘NKT’(T细胞和NK细胞标记物)的情况也知之甚少。一个主要的功能定义的NKT亚群CD1d反应性NKT和靶CD1d高度保守，在启动和控制抗病毒反应中发挥作用，但也可以引起模型肝炎。我们已经鉴定出人肝CD1D反应性NKT。这项建议将确定丙型肝炎病毒感染中的人肝CD1d反应性NKT是否具有促炎的功能潜力。我们将检验这一假设，即虽然CD1d反应性NKT在我们定义的新的MHC-I类途径中，在急性抗病毒反应中对感染的CD1d+肝细胞产生自然反应，但它们的慢性刺激有助于肝脏病理。反过来，我们还提出肝细胞可以损伤CD1d反应性NKT。最后，我们还将确定独特的肝脏形式的CD1d在丙型肝炎病毒感染的肝脏中表达的位置。 目的1.验证肝脏CD1d反应性NKT在慢性丙型肝炎中可能作为促炎和促纤维化细胞，并可能参与肝损伤的假说。 目的2.体外研究丙型肝炎病毒感染是否增加体内CD1d的表达，增强肝脏CD1d反应性NKT对CD1d的识别能力。 这项研究将提供关于肝脏CD1d-NKT细胞‘AXIS’是否是新的丙型肝炎病毒感染治疗干预措施的合适靶点，以及在黑猩猩急性丙型肝炎感染以及肝脏免疫学和‘NKT’细胞方面与其他合作者和P.I.互补的信息。

DESCRIPTION (provided by applicant): Worldwide nearly 200 million people are infected with HCV. Close to 2% of the U.S. population are infected with HCV, and levels in some demographic groups are much higher. In most cases, exposure to HCV results in persistent chronic infection and the majority of cases remain undetected until symptomatic. Immunosuppression, whether due to co-infection with any of several pathogens or due to treatment, enhances HCV-mediated disease progression substantially. Hence HCV infection will remain a major long-term public health burden. Despite recent evidence that failure of the immune response early in HCV infection results in persistence, little is known of the first line defense, innate immunity. There is considerable information about peripheral blood T cells in HCV infection, but little is also known of the approximately 25% intrahepatic lymphocytes (IHL) that are 'NKT' (both T & NK cell markers). A major functionally-defined NKT subset, CD1d-reactive NKT and target, CD1d, are highly conserved and have roles in initiation and control of antiviral responses, but can also cause model hepatitis. We have identified human hepatic CD 1d-reactive NKT. This proposal will determine whether human hepatic CD1d-reactive NKT in HCV infection have the functional potential to be pro-inflammatory. We will test the hypothesis that while CD1d-reactive NKT naturally respond to infected CD 1d+ liver cells during acute anti-viral responses in a novel MHC class-I like path we have defined, their chronic stimulation contributes to liver pathology. Reciprocally, we also propose that hepatocytes can damage CD1d-reactive NKT. Finally, we will also determine where the unique hepatic form of CD1d is expressed in HCV infected liver. Aim 1. Test the hypothesis that hepatic CD1d-reactive NKT may serve as pro-inflammatory and profibrotic cells in chronic HCV-mediated hepatitis and potentially contribute to liver injury. Aim 2. Determine whether HCV infection increases CD1d expression in vivo and enhances recognition of the hepatic form of CD1d by hepatic CD1d-reactive NKT in vitro. This study will provide information on whether the hepatic CD1d-NKT cell 'axis' is a suitable target for novel therapeutic interventions in HCV infection and are complementary to others of the collaborators and P.I. on acute HCV infection in chimpanzees, as well as on liver immunology and on 'NKT' cells in general.