Innate-like hepatic CD1d-reative NKT cells:Liver Disease

全世界有近2亿人感染了丙型肝炎病毒。近2%的美国人口被感染 与丙型肝炎病毒，而且在一些人口群体的水平要高得多。在大多数情况下，接触丙型肝炎病毒结果 在持续性慢性感染中，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，都会增强 丙型肝炎病毒介导的疾病实质上进展。因此，丙型肝炎病毒感染仍将是主要的长期公众 健康负担。尽管最近有证据表明，丙型肝炎病毒感染早期免疫反应失败会导致 在坚持中，人们对第一道防线--先天免疫知之甚少。有相当多的信息 关于外周血T细胞在丙型肝炎病毒感染中的作用，但对肝内~25%的T细胞也知之甚少 是‘NKT’的淋巴细胞(包括T和NK细胞标记物)。主要功能定义的NKT子集， CDLD反应性NKT和靶分子CDLD高度保守，在抗-HBs的启动和调控中发挥作用。 病毒反应，但也可引起模型肝炎。我们已经鉴定出人肝Cd-ld反应性NKT。 这项建议将确定丙型肝炎病毒感染中的人肝CDLD反应性NKT是否具有 具有促炎的功能潜力。我们将检验这样的假设：当CDLD反应性NKT 在一种新的类MHC中，在急性抗病毒反应中自然对感染的CD1D？肝细胞做出反应 我们已经定义的路径，他们的慢性刺激有助于肝脏病理。作为回报，我们还 提示肝细胞可损伤CDLD反应性NKT。最后，我们还将确定唯一的 在丙型肝炎病毒感染的肝脏中表达肝脏形式的CDLD。 目的1.验证肝脏CDLD反应性NKT可能具有促炎和促炎症作用的假说。 肝纤维化细胞在慢性丙型肝炎中的作用，并可能与肝损伤有关。 目的2.确定丙型肝炎病毒感染是否增加体内CDLD的表达并增强 肝脏CDLD反应性NKT对CDLD肝脏形态的识别作用 这项研究将提供关于肝脏CDLD-NKT细胞轴是否适合作为靶点的信息。 丙型肝炎病毒感染的新治疗干预措施，与其他合作者和 P.I.对黑猩猩的急性丙型肝炎病毒感染，以及对肝脏免疫学和一般的NKT细胞的影响。

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. Irnmunosuppression, 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 ~25% intrahepatic lymphocytes (IHL) that are 'NKT' (both T & NK cell markers). A major functionally-defined NKT subset, CDld-reactive NKT and target, CDld, are highly conserved and have roles in initiation and control of anti- viral responses, but can also cause model hepatitis. We have identified human hepatic CD ld-reactive NKT. This proposal will determine whether human hepatic CDld-reactive NKT in HCV infection have the functional potential to be pro-inflammatory. We will test the hypothesis that while CDld-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 CDld-reactive NKT. Finally, we will also determine where the unique hepatic form of CDld is expressed in HCV infected liver. Aim 1. Test the hypothesis that hepatic CDld-reactive NKT may serve as pro-inflammatory and pro- fibrotic cells in chronic HCV-mediated hepatitis and potentially contribute to liver i_ury. Aim 2. Determine whether HCV infection increases CDld expression in vivo and enhances recognition of the hepatic form of CDld by hepatic CDld-reactive NKT in vitro. This study will provide information on whether the hepatic CDld-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.