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

先天性肝脏 CD1d 反应性 NKT 细胞：肝脏疾病

• 批准号: 6945687
• 负责人: MARK A EXLEY
• 金额: $ 21.25万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6945687
• 关键词: CD1 molecule; T cell receptor; apoptosis; biopsy; cell line; chemokine; clinical research; cytotoxicity; enzyme linked immunosorbent assay; fibrosis; flow cytometry; hepatitis C; hepatitis C virus; human subject; immune response; inflammation; leukocyte activation /transformation; liver cells; microorganism immunology; natural killer cells; receptor expression; virus protein

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.

描述（由申请人提供）：全球有近2亿人感染HCV。接近2%的美国人感染了丙型肝炎病毒，在一些人口统计群体中的水平要高得多。在大多数情况下，接触丙型肝炎病毒会导致持续性慢性感染，大多数病例直到出现症状才被发现。免疫抑制，无论是由于与几种病原体中的任何一种共同感染，还是由于治疗，都会大大增强hcv介导的疾病进展。因此，丙型肝炎病毒感染仍将是一个主要的长期公共卫生负担。尽管最近有证据表明，HCV感染早期免疫反应的失败会导致持续存在，但人们对第一道防线——先天免疫知之甚少。关于HCV感染中的外周血T细胞有相当多的信息，但对于大约25%的肝内淋巴细胞（IHL）是“NKT”（T和NK细胞标记）知之甚少。一个主要的功能性定义的NKT亚群，CD1d反应性NKT和靶标CD1d，是高度保守的，在抗病毒反应的启动和控制中起作用，但也可以引起模型肝炎。我们已经鉴定出人类肝脏cd1d反应性NKT。本研究将确定HCV感染中人类肝脏cd1反应性NKT是否具有促炎的功能潜力。我们将验证这样的假设：虽然cd1d反应性NKT在急性抗病毒反应中对受感染的cd1d +肝细胞有自然反应，但它们的慢性刺激有助于肝脏病理。反过来，我们也提出肝细胞可以损害cd1反应性NKT。最后，我们还将确定在HCV感染的肝脏中CD1d的独特肝脏形式的表达位置。