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

基本信息

批准号：
7262619
负责人：
MARK A EXLEY
金额：
$ 20.15万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/7262619
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

项目摘要

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）：全世界有近 2 亿人感染 HCV。近 2% 的美国人口感染 HCV，某些人群的感染水平要高得多。在大多数情况下，接触丙肝病毒会导致持续性慢性感染，并且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一个重大的长期公共卫生负担。尽管最近有证据表明丙型肝炎病毒感染早期免疫反应失败会导致病毒持续存在，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 细胞有大量信息，但对于大约 25% 的肝内淋巴细胞 (IHL) 是“NKT”（T 和 NK 细胞标记物）知之甚少。一个主要的功能定义的 NKT 子集，CD1d 反应性 NKT 和靶点 CD1d，高度保守，在抗病毒反应的启动和控制中发挥作用，但也可能引起模型肝炎。我们已经鉴定出人肝 CD 1d 反应性 NKT。该提案将确定 HCV 感染中人肝 CD1d 反应性 NKT 是否具有促炎的功能潜力。我们将测试以下假设：虽然 CD1d 反应性 NKT 在我们定义的新型 MHC I 类路径中的急性抗病毒反应期间自然对感染的 CD1d+ 肝细胞做出反应，但它们的慢性刺激会导致肝脏病理学。相反，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 CD1d 的独特肝脏形式在 HCV 感染的肝脏中表达的位置。目标 1. 检验以下假设：肝脏 CD1d 反应性 NKT 可能在慢性 HCV 介导的肝炎中充当促炎细胞和促纤维化细胞，并可能导致肝损伤。目标 2. 确定 HCV 感染是否会增加体内 CD1d 表达，并在体外增强肝脏 CD1d 反应性 NKT 对肝脏形式 CD1d 的识别。这项研究将提供关于肝脏 CD1d-NKT 细胞“轴”是否是 HCV 感染新型治疗干预的合适靶点的信息，以及是否与其他合作者和 P.I. 的补充。黑猩猩急性丙型肝炎病毒感染、肝脏免疫学和“NKT”细胞的总体情况。