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: 7489769
• 负责人: MARK A EXLEY
• 金额: $ 10.2万
• 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/7489769
• 关键词: Acute; Anti-Inflammatory Agents; Anti-inflammatory; Antiviral Response; Apoptosis; Apoptotic; Area; Blood; Bone Marrow; Cells; Characteristics; Chronic; Disease; Disease Progression; Exposure to; Failure; Family; Goals; Hepatic; Hepatitis; Hepatitis C; Hepatitis C virus; Hepatocyte; Human; Immune response; Immunity; Immunobiology; Immunology; Immunosuppression; In Vitro; Infection; Inflammatory; Injury to Liver; Liver; Liver diseases; Lymphocyte; MHC Class I Genes; Mediating; Modeling; Natural Immunity; Natural Killer Cells; Nature; Numbers; Pan Genus; Pan troglodytes; Pathology; Physiological; Population; Principal Investigator; Proteins; Public Health; Role; T-Lymphocyte; Testing; Therapeutic Intervention; Therapeutic immunosuppression; Tissues; Viral Proteins; chemokine; cytokine; cytotoxic; in vivo; intrahepatic; member; novel; novel therapeutics; pathogen; peripheral blood; programs; response

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.

全世界有近2亿人感染HCV。近2%的美国人口被感染 在某些人口群体中，HCV的水平要高得多。在大多数情况下，暴露于HCV导致 在持续的慢性感染中，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的共感染还是由于治疗， 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众 健康负担。尽管最近的证据表明，HCV感染早期免疫应答的失败导致了HCV感染的发生。 在持久性方面，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HCV感染中外周血T细胞的研究，但对约25%的肝内T细胞也知之甚少。 淋巴细胞（IHL）是“NKT”（T和NK细胞标志物）。一个主要的功能定义的NKT子集， CDld反应性NKT和靶CDld是高度保守的，并且在抗CDld的起始和控制中起作用。 病毒反应，但也可能导致模型肝炎。我们已经鉴定了人肝CD ld反应性NKT。 该提议将确定HCV感染中人肝CDld反应性NKT是否具有 功能性潜在的促炎性。我们将检验一个假设，即CDld反应性NKT 在一种新的MHC I类抗原中，在急性抗病毒反应期间自然地对感染的CD 1d <$肝细胞产生反应 虽然我们已经定义了这条路径，但它们的慢性刺激有助于肝脏病理学。反过来，我们也 提出肝细胞可损伤CDld反应性NKT。最后，我们还将确定 肝脏形式的CD 1d在HCV感染的肝脏中表达。 目标1.检验肝脏CDld反应性NKT可能作为促炎和促炎因子的假设。 慢性HCV介导的肝炎中的纤维化细胞，并可能导致肝损伤。 目标2.确定HCV感染是否在体内增加CDld表达并增强CDld表达。 体外肝CDld反应性NKT识别肝形式的CDld。 这项研究将提供关于肝CDld-NKT细胞“轴”是否是一个合适的靶点的信息。 HCV感染的新型治疗干预措施，是对其他合作者的补充， P.I.在黑猩猩的急性HCV感染，以及肝脏免疫学和一般的“NKT”细胞上。