Regulation of hepatic NKT cells by CDld+ liver cells

CD1d肝细胞对肝NKT细胞的调节

• 批准号: 7990927
• 负责人: MARK A EXLEY
• 金额: $ 22.69万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-28 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7990927
• 关键词: Acids; Acute; Blood; Cell Fraction; Cell-Free System; Cells; Cessation of life; Chronic; Chronic Hepatitis; Chronic Hepatitis C; Cirrhosis; Cytolysis; Data; Development; Disease Progression; Environment; Fibrosis; Gene Expression; Hepatic; Hepatitis C; Hepatitis C virus; Hepatocyte; Human; Immune; Immunity; In Vitro; Incidence; Infection; Inflammation; Inflammatory; Lead; Leukocytes; Libraries; Ligands; Lipids; Literature; Liver; Liver diseases; Location; Mammals; Natural Killer Cells; Patients; Physiological; Population; Population Heterogeneity; Primary carcinoma of the liver cells; Public Health; Reagent; Recombinants; Regulation; Regulatory T-Lymphocyte; Relative (related person); Reporting; Risk Factors; Rodent; Role; Screening procedure; Specificity; Stimulus; System; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tumor Immunity; Viral; Virus Diseases; adaptive immunity; base; cellular targeting; cytokine; human tissue; in vivo; killer T cell; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pre-clinical; public health relevance; response; small molecule; tumor

DESCRIPTION (provided by applicant): Worldwide, nearly 200 million people have hepatitis C virus (HCV), the great majority of which have chronic hepatitis, nearly 2% in the U.S. are infected with HCV, a major public health challenge with ~9,000 U.S. deaths / yr. currently. Chronic hepatitis frequently leads to cirrhosis, which in turn is the major risk factor for hepatocellular carcinoma (HCC). Although roles of specific immunity in acute and chronic hepatitis C (CHC) are emerging, little is known about key liver immune subset changes with progression. Adaptive HCV-specific T cells are concentrated in liver with innate-like natural killer (NK) and NKT, which represent to ~50% of normal and diseased liver leukocytes. Hepatic NKT are implicated in protection against acute viral infection, but maybe subverted by HCV. Regulation of activation of hepatic NKT cells is poorly understood. This proposal is to determine mechanisms by which the major and heterogeneous population of human hepatic NKT, that we first functionally defined, are regulated by CD1d+ liver cells in hepatitis C. Based on our findings, we hypothesize that in chronic hepatitis C, this large heterogeneous population of liver NKT, instead of being protective, promote inflammation and fibrosis, believed to be prerequisites for development of HCC. We propose that hepatic CD1d can present novel lipid ligands to liver NKT cells. We have evidence for ligand(s) for hepatic NKT and we have isolated fractions from CD1d+ cells that stimulate iNKT selectively. These data provide proof-of-principle that we can obtain fractions with ligand-like activity for NKT. This proposal will exploit our unique expertise with human hepatic and control NKT, physiological CD1d+ presenting liver cells, and reagents we and collaborators have developed to identify hepatic NKT- activating fractions and potential ligands from lipid libraries, to provide target(s) for preclinical development of potential novel therapeutic interventions in CHC and HCC. Given deleterious effects of chronic NKT stimulation we have uncovered, this will enable us to potentially manipulate hepatic NKT through novel molecule(s) toward novel therapeutics to help delay progression to cirrhosis and HCC in hepatitis C. Aim 1. Establish a representative panel of human hepatic CD1d-reactive NKT cells and test candidate small molecules for specific activation or inhibition of hepatic NKT cells vs. blood invariant NKT cells. 1a. Prepare and functionally characterize enriched hepatic NKT panels for use alongside our iNKT. 1b. Determine which iNKT ligands from a selective library also activate hepatic NKT and which inhibit. Aim 2. Determine specificity of human hepatic NKT for hepatic vs. other CD1d+ target cells, and define hepatic CD1d+ cell fractions that specifically activate or inhibit hepatic NKT. 2a. Determine whether enriched hepatic NKT cells have distinct fine specificity for hepatic vs. other CD1d+ target cells relative to iNKT cells. 2b. Identify fractions of eluted liver CD1d ligands that specifically activate hepatic NKT and/or iNKT. PUBLIC HEALTH RELEVANCE: Worldwide nearly 200 million people have hepatitis C and many of these will progress to develop complications of the infection, including cirrhosis and hepatocellular carcinoma. This proposal is to study and manipulate a major immune population in the human liver, 'NKT' cells, which while protective in acute infections appear to contribute to inflammatory and fibrotic damage leading to liver disease progression.

描述（由申请人提供）：全世界有近 2 亿人感染丙型肝炎病毒 (HCV)，其中绝大多数患有慢性肝炎，美国近 2% 的人感染 HCV，这是一项重大的公共卫生挑战，美国每年约有 9,000 人死亡。现在。慢性肝炎经常导致肝硬化，而肝硬化又是肝细胞癌（HCC）的主要危险因素。尽管特异性免疫在急性和慢性丙型肝炎 (CHC) 中的作用正在显现，但人们对关键肝脏免疫亚群随病情进展的变化知之甚少。适应性 HCV 特异性 T 细胞集中在肝脏中，具有先天性自然杀伤 (NK) 和 NKT，约占正常和患病肝脏白细胞的 50%。肝脏 NKT 与预防急性病毒感染有关，但可能会被 HCV 破坏。人们对肝脏 NKT 细胞激活的调节知之甚少。该提案旨在确定我们首先在功能上定义的人类肝脏 NKT 的主要异质群体在丙型肝炎中受到 CD1d+ 肝细胞调节的机制。根据我们的发现，我们假设在慢性丙型肝炎中，这种大量的肝脏 NKT 异质群体非但没有起保护作用，反而促进了炎症和纤维化，这被认为是发展为慢性丙型肝炎的先决条件。 肝癌。我们认为肝脏 CD1d 可以向肝脏 NKT 细胞呈递新型脂质配体。我们有肝脏 NKT 配体的证据，并且我们从 CD1d+ 细胞中分离出选择性刺激 iNKT 的组分。这些数据提供了原理证明，证明我们可以获得具有 NKT 配体样活性的级分。该提案将利用我们在人类肝脏和对照 NKT、生理性 CD1d+ 呈递肝细胞以及我们和合作者开发的试剂方面的独特专业知识，从脂质库中识别肝脏 NKT 激活组分和潜在配体，为 CHC 和 HCC 潜在新型治疗干预措施的临床前开发提供靶标。鉴于我们已经发现的慢性 NKT 刺激的有害影响，这将使我们能够通过新分子操纵肝脏 NKT 以获得新的治疗方法，以帮助延缓丙型肝炎向肝硬化和 HCC 的进展。 目标 1. 建立人类肝脏 CD1d 反应性 NKT 细胞的代表性小组，并测试候选小分子对肝脏的特异性激活或抑制 NKT 细胞与血液不变 NKT 细胞。 1a.准备和功能表征富集的肝脏 NKT 组合，以便与我们的 iNKT 一起使用。 1b.确定选择性文库中哪些 iNKT 配体也激活肝脏 NKT，哪些抑制。目标 2. 确定人肝脏 NKT 对肝脏与其他 CD1d+ 靶细胞的特异性，并定义特异性激活或抑制肝脏 NKT 的肝脏 CD1d+ 细胞组分。 2a.确定富集的肝脏 NKT 细胞相对于 iNKT 细胞是否对肝脏与其他 CD1d+ 靶细胞具有明显的精细特异性。 2b.鉴定特异性激活肝脏 NKT 和/或 iNKT 的洗脱肝脏 CD1d 配体的部分。 公共卫生相关性：全世界有近 2 亿人患有丙型肝炎，其中许多人会发展为感染并发症，包括肝硬化和肝细胞癌。该提案旨在研究和操纵人类肝脏中的主要免疫群体“NKT”细胞，该细胞虽然在急性感染中具有保护作用，但似乎会导致炎症和纤维化损伤，从而导致肝病进展。