Role of HCV* Hepatocyte in Regulation of Antiviral T cell Immunity

HCV* 肝细胞在抗病毒 T 细胞免疫调节中的作用

• 批准号: 7919878
• 负责人: Young S. Hahn
• 金额: $ 23.23万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7919878
• 关键词: Acute; Antiviral Agents; Apoptosis; Be++ element; Beryllium; CD4 Positive T Lymphocytes; CD8B1 gene; CTLA4 gene; Cell physiology; Cells; Chronic; Coculture Techniques; Development; Discontinuous Capillary; Epigenetic Process; Functional disorder; Genes; Genome; Hepatitis C; Hepatitis C virus; Hepatocyte; Human; Immune; Immunity; Impairment; Infection; Interferon Type II; Interleukin-17; Interleukin-2; Ligands; Liver; Liver Cirrhosis; Mediating; Outcome; Patients; Play; Population; Primary carcinoma of the liver cells; Production; Proteins; Regulation; Research; Role; Shapes; Site; Staging; T cell differentiation; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Viral; adaptive immunity; base; cytokine; design; insight; interleukin-22; transcription factor

The project 2 of HCV Cooperative Research Center alms to understand the regulation of adaptive Immunity via the Interaction of HCV-infected hepatocytes with CD4 T cells during acute HCV Infection. HCV Infection In humans is remarkably efficient In establishing viral persistence, leading to the development of liver cirrhosis and hepatocellular carcinoma. CDS T cells are Involved in controlling HCV Infection; but. In chronic HCV patients, severe CD4 and CDS T cell dysfunction has been observed. This suggests that HCV may employ some mechanism to counteract or possibly suppress the host T cell response. The primary site of viral replication is within hepatocytes in the liver. During HCV Infection, there is the increased population of CD4 T cells in the liver sinusoid, which allows close contact with HCV-infected hepatocytes. To determine whether the Interaction of HCV-infected hepatocytyes with CD4 T cells alters CD4 T cell helper function on shaping CDS T cell effector antiviral activity, we conducted co-culture studies of HCV-infected hepatocytes with CD4 T cells. Our preliminary studies, we demonstrated that hepatocytes expressing whole HCV proteins (I.e. HCV+ hepatocytes) upregulated the ligand of PD-1 negative costimulatory molecule, B7-H1, and TGF-b synthesis. In addition, HCV+ hepatocytes are capable of impairing CD4 T cell function including Inhibition of IFN-g production. Based on these findings, we hypothesize that HCV+ hepatocyte-mediated Inhibition of CD4 T cell function plays a pivotal role In Impairing antiviral CDS T cell effector function. To test this hypothesis, we propose three specific alms, we will first explore the mechanism for HCV+ hepatocytemediated Inhibition of CD4 T cell responses. Second, we will determine the impact of HCV+ hepatocyteinduced CD4 T cell dysfunction on regulating antiviral CDS T cell effector function. Lastly, we will examine the status of CD4 T cell differentiation and correlate it with the outcome of HCV infection during acute HCV patients. Results of these studies will provide valuable insight Into designing therapeutic strategies against to HCV Infection.

丙型肝炎合作研究中心项目2旨在了解获得性免疫的调节 通过急性HCV感染期间HCV感染的肝细胞与CD 4 T细胞的相互作用。HCV感染 在人类中是非常有效的建立病毒的持久性，导致肝脏的发展 肝硬化和肝细胞癌CDS T细胞参与控制HCV感染;但是。慢性 HCV患者中，已观察到严重的CD 4和CDS T细胞功能障碍。这表明HCV可能 采用某种机制来抵消或可能抑制宿主T细胞应答。的原发部位 病毒复制是在肝脏中的肝细胞内进行的。在HCV感染期间， 肝窦中的CD 4 T细胞，可与HCV感染的肝细胞密切接触。以确定 HCV感染的肝细胞与CD 4 T细胞的相互作用是否改变了CD 4 T细胞辅助功能， 为了塑造CDS T细胞效应抗病毒活性，我们进行了HCV感染肝细胞的共培养研究， CD 4 T细胞我们的初步研究表明，表达完整HCV的肝细胞 蛋白质（即HCV+肝细胞）上调PD-1阴性共刺激分子B7-H1的配体， 和TGF-β合成。此外，HCV+肝细胞能够损害CD 4 T细胞功能，包括 IFN-γ产生的抑制。基于这些发现，我们假设HCV+肝细胞介导的 CD 4 T细胞功能的抑制在损害抗病毒CD 4 T细胞效应子功能中起关键作用。测试 针对这一假设，我们提出了三种特异性的救济措施，我们将首先探讨HCV+肝细胞介导的机制， 抑制CD 4 T细胞应答。其次，我们将确定HCV+肝细胞诱导的影响， CD 4 T细胞功能障碍对调节抗病毒CDS T细胞效应子功能的影响。最后，我们将研究 急性HCV感染时CD 4 T细胞分化状态及其与HCV感染转归的关系 患者这些研究的结果将为设计治疗策略提供有价值的见解， HCV感染。