Role of Inflammatory B cells in Liver Fibrosis and Chronic HCV Infection

炎症 B 细胞在肝纤维化和慢性 HCV 感染中的作用

• 批准号: 8648419
• 负责人: Manoj Thapa
• 金额: $ 5.51万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8648419
• 关键词: Affect; Antibody Formation; Antibody-Producing Cells; Antigen-Antibody Complex; Antiviral Agents; B Cell Proliferation; B cell differentiation; B-Cell Activation; B-Cell Lymphomas; B-Lymphocyte Subsets; B-Lymphocytes; Binding; Biological Assay; CD4 Positive T Lymphocytes; Carbon Tetrachloride; Cell Communication; Cell Proliferation; Cell Survival; Cell Therapy; Cell physiology; Cells; Cessation of life; Chronic; Chronic Hepatitis C; Cirrhosis; Clinical; Clinical Research; Coculture Techniques; Cryoglobulinemia; Data; Dendritic Cells; Disease; Epidemiologic Studies; Epitopes; Ethanol; Fibrosis; Frequencies; Functional disorder; Goals; Hepatic; Hepatic Fibrogenesis; Hepatic Stellate Cell; Hepatitis C; Hepatitis C virus; Hepatocyte; Human; Immune; Immune response; Immunoglobulins; In Vitro; Individual; Indolent; Infection; Inflammatory; Ligation; Liver; Liver Failure; Liver Fibrosis; Liver diseases; Lymphoma; Lymphoproliferative Disorders; Malignant Neoplasms; Mediating; Memory; Modeling; Molecular; Mus; Non-Hodgkin' s Lymphoma; Outcome; Pathogenesis; Patients; Phenotype; Population; Positioning Attribute; Primary carcinoma of the liver cells; Process; Production; Retinoids; Role; Specimen; System; T-Lymphocyte; Testing; Therapeutic Intervention; Tretinoin; United States; Viral; Virus Diseases; Vitamin A; Work; bile duct; chronic liver disease; cytokine; design; exhaustion; fibrogenesis; in vivo; intrahepatic; liver transplantation; mouse model; nonalcoholic steatohepatitis; novel; peripheral blood; problem drinker; public health relevance

DESCRIPTION (provided by applicant): More than 170 million people worldwide are infected with hepatitis C virus (HCV) and the majority are unable to resolve the infection and remain persistently infected. A significant number of these individuals will go on to develop severe complications including liver fibrosis, cirrhosis, and hepatocellular carcinoma. HCV is a leading cause of liver failure and transplantation in the United States with approximately 15,000 HCV-associated deaths each year. Persistent infection is characterized by a poor antiviral T cell immune response. The early CD4+ T cell exhaustion, CTL viral epitope escape, dendritic cells (DC) dysfunction and viral evasion of immune recognition contribute to persistent viral infection. However, the immunological function of B cells and antibody responses during chronic HCV infection remains elusive. The chronic HCV infection is characterized by progressive liver fibrosis largely mediated by a nonparenchymal cell population known as hepatic stellate cells (HSC), which mainly store vitamin A (e.g. retinoids) in the liver. HSC reside in the space between the endothelial layer and parenchymal hepatocytes, and this anatomical position enables HSC to interact both with the infected hepatocytes and infiltrating immune cells. During chronic HCV infection, HSC transition from a state of quiescence to activation. Although many studies have described the effect of this HSC transition on fibrogenesis, the correlation between HSC frequency and B cell phenotype and function in the liver during chronic hepatitis C infection is unclear. The objective of this study is to understand the molecular interaction between HSC and B cells during HCV infection and determine how these interactions would affect the outcome of immune responses in the liver. We will approach these questions from four different directions: (i) to determine HSC-B cell interaction in vitro and identify the key molecules that instruct the fate of the B cells using primary murine HSC and B cells; (ii) to determine the specific role of B cells in liver fibrosis using in vivo murine models of liver fibrosis; (iii) characterize the B cell subsets phenotypes and functions in the liver and peripheral blood of chronically infected human HCV patients; and (iv) to compare the effects of chronic HCV infection to non-alcoholic steatohepatitis (NASH) and alcoholic (ETOH) liver diseases on consequent modulations in B cell functions. Overall, our goal is to understand the role of HSC and B cells in hepatic fibrosis during chronic liver diseases and their contribution to hepatic as well as extra-hepatic manifestations in humans. As B cells are primary cells that produce immunoglobulins, a number of novel cell-based therapies can be explored by targeting B cell function during chronic HCV infection.

描述（由申请人提供）：全世界有超过1.7亿人感染丙型肝炎病毒（HCV），大多数人无法解决感染并保持持续感染。这些人中的相当一部分将继续发展严重的并发症，包括肝纤维化，肝硬化和肝细胞癌。在美国，丙型肝炎病毒是导致肝衰竭和移植的主要原因，每年约有15，000例与丙型肝炎病毒相关的死亡。持续性感染的特征是抗病毒T细胞免疫应答差。早期CD 4 + T细胞耗竭、CTL病毒表位逃逸、树突状细胞（DC）功能障碍和病毒逃避免疫识别是导致病毒持续感染的重要原因。然而，慢性HCV感染期间B细胞的免疫功能和抗体应答仍然是难以捉摸的。慢性HCV感染的特征在于进行性肝纤维化，主要由称为肝星状细胞（HSC）的非实质细胞群介导，其主要在肝脏中储存维生素A（例如类维生素A）。HSC存在于内皮层和实质肝细胞之间的空间中，并且该解剖位置使得HSC能够与受感染的肝细胞和浸润的免疫细胞两者相互作用。在慢性HCV感染期间，HSC从静止状态转变为活化状态。虽然许多研究已经描述了这种HSC转变对纤维形成的影响，但慢性丙型肝炎感染期间肝中HSC频率与B细胞表型和功能之间的相关性尚不清楚。本研究的目的是了解HCV感染过程中HSC和B细胞之间的分子相互作用，并确定这些相互作用如何影响肝脏免疫应答的结果。我们将从四个不同的方向来探讨这些问题：（i）利用原代小鼠HSC和B细胞来确定HSC-B细胞的体外相互作用，并鉴定指导B细胞命运的关键分子;（ii）利用小鼠肝纤维化的体内模型来确定B细胞在肝纤维化中的特定作用;（iii）表征慢性感染的人HCV患者的肝和外周血中的B细胞亚群表型和功能;和（iv）比较慢性HCV感染与非酒精性脂肪性肝炎（NASH）和酒精性（ETOH）肝病对B细胞功能的后续调节的影响。总的来说，我们的目标是了解HSC和B细胞在慢性肝病肝纤维化中的作用，以及它们对人类肝脏和肝外表现的贡献。由于B细胞是产生免疫球蛋白的原代细胞，因此可以通过靶向慢性HCV感染期间的B细胞功能来探索许多新型基于细胞的疗法。