Regulation of hepatic NKT cells by CDld+ liver cells

CD1d肝细胞对肝NKT细胞的调节

• 批准号: 8100457
• 负责人: MARK A EXLEY
• 金额: $ 18.35万
• 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/8100457
• 关键词: Acids; Acute; Acute Hepatitis; 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）：全球范围内有近2亿人患有丙型肝炎病毒（HCV），其中大多数患有慢性肝炎，在美国，近2％的人感染了HCV，这是一项主要的公共卫生挑战，这是美国9,000次死亡人数约9,000人。现在。慢性肝炎经常导致肝硬化，这反过来是肝细胞癌（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）中的作用正在出现，但对随着进展的关键肝脏免疫子群的变化知之甚少。自适应HCV特异性T细胞浓缩具有先天天然杀手（NK）和NKT的肝脏，占正常和患病的肝白细胞的约50％。肝NKT与防御急性病毒感染有关，但可能被HCV颠覆。肝NKT细胞激活的调节尚不清楚。 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。我们建议肝CD1D可以向肝NKT细胞呈现新颖的脂质配体。我们有肝NKT配体配体的证据，并且有选择性地刺激INKT的CD1D+细胞中分离出的分数。这些数据提供了原理证明，我们可以获得NKT具有类似配体活性的分数。该建议将通过人类肝和控制NKT，生理CD1D+呈现肝细胞来利用我们的独特专业知识，而我们和合作者已经开发了试剂，以识别肝NKT激活分数和脂质图书馆的潜在配体，以提供靶标的，以提供潜在的新型Theraphe Theraphe Theraphe Theraphe Theraphe Theraphe Theraphe Theraphe Theraphicut Interpairitic Interpairitic in Chc and Hcc和Hccc和Hccc和Hcc。鉴于我们已经发现了慢性NKT刺激的有害作用，这将使我们能够通过新型分子（S）对新型治疗剂进行潜在操纵肝NKT，以帮助延迟到肝炎和肝炎中的肝硬化和HCC。目标1。 NKT细胞与血液不变的NKT细胞。 1a。准备并在功能上表征富集的肝NKT面板，可与我们的inkt一起使用。 1B。确定选择性文库中哪些iNKT配体也激活肝NKT并抑制哪些iNKT。 AIM 2。确定人肝NKT对肝和其他CD1D+靶细胞的特异性，并定义专门激活或抑制肝NKT的肝CD1D+细胞级分。 2a。确定相对于Inkt细胞，富集的肝NKT细胞对肝和其他CD1D+靶细胞的特异性是否不同。 2b。确定专门激活肝NKT和/或INKT的洗脱肝CD1D配体的分数。 公共卫生相关性：全球近2亿人患有丙型肝炎，其中许多人将进展发展以发展感染并发症，包括肝硬化和肝细胞癌。该建议是研究和操纵人肝脏“ NKT”细胞中的主要免疫群体，尽管急性感染的保护作用似乎导致炎症和纤维化损伤，从而导致肝病进展。

项目成果

Human invariant NKT cell subsets differentially promote differentiation, antibody production, and T cell stimulation by B cells in vitro.

人类恒定 NKT 细胞亚群在体外有差异地促进 B 细胞的分化、抗体产生和 T 细胞刺激。

• DOI: 10.4049/jimmunol.1202223
• 发表时间: 2013
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Zeng,ShijuanGrace;Ghnewa,YasmeenG;O'Reilly,VincentP;Lyons,VictoriaG;Atzberger,Ann;Hogan,AndrewE;Exley,MarkA;Doherty,DerekG
• 通讯作者: Doherty,DerekG

CD1d favors MHC neighborhood, GM1 ganglioside proximity and low detergent sensitive membrane regions on the surface of B lymphocytes.

CD1d 有利于 B 淋巴细胞表面的 MHC 邻近区域、GM1 神经节苷脂邻近区域和低去污剂敏感膜区域。

• 发表时间: 2014
• 期刊: Biochimica et biophysica acta
• 作者: Shrestha,Dilip;Exley,MarkA;Vereb,György;Szöllősi,János;Jenei,Attila
• 通讯作者: Jenei,Attila