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: 7100881
• 负责人: MARK A EXLEY
• 金额: $ 20.75万
• 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/7100881
• 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）：全球近2亿人感染了HCV。近2％的美国人口感染了HCV，一些人口组中的水平要高得多。在大多数情况下，暴露于HCV会导致持续性慢性感染，并且大多数病例仍未发现直到有症状。免疫抑制，无论是由于与几种病原体的任何共同感染，还是由于治疗而引起的，都会显着增强HCV介导的疾病进展。因此，HCV感染将仍然是重大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导致持久性，但对第一线防御，先天免疫知之甚少。关于HCV感染中外周血T细胞的信息很大，但在大约25％的肝内淋巴细胞（IHL）中，几乎不知道NKT'（T＆NK细胞标记）。功能定义的主要定义的NKT子集，CD1D反应性NKT和靶标CD1D具有高度保守，并且在抗病毒反应的启动和控制中具有作用，但也可能导致模型肝炎。我们已经确定了人类肝CD 1D反应性NKT。该建议将确定HCV感染中人类肝CD1D反应性NKT是否具有促炎的功能潜力。我们将检验以下假设：尽管在我们定义的新型MHC类I类中，在急性抗病毒反应过程中，CD1D反应性NKT自然对感染的CD 1D+肝细胞反应，但它们的慢性刺激有助于肝脏病理。相互地，我们还建议肝细胞会损害CD1D反应性NKT。最后，我们还将确定在HCV感染的肝脏中表达CD1D的唯一肝形式。 AIM 1。检验以下假设：肝CD1D反应性NKT可以作为慢性HCV介导的肝炎的促炎和纤维化细胞，并可能导致肝损伤。 AIM 2。确定HCV感染是否会增加体内CD1D的表达，并通过体外肝CD1D反应性NKT在体外增强对CD1D的肝形式的识别。 这项研究将提供有关肝CD1D-NKT细胞“轴”是否是HCV感染中新型治疗干预措施的合适靶标，并且与其他合作者和P.I互补。关于黑猩猩的急性HCV感染以及肝脏免疫学和一般的“ NKT”细胞。