Immune regulation and co-stimulation in treatment outcome of chronic hepatitis B

免疫调节与共刺激对慢性乙型肝炎治疗效果的影响

• 批准号: 8545811
• 负责人: Kyong-Mi Chang
• 金额: $ 49.75万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8545811
• 关键词: Acute Hepatitis; Antiviral Agents; Antiviral Therapy; Cell physiology; Chronic; Chronic Hepatitis; Chronic Hepatitis B; Cirrhosis; Clinical; Cross-Sectional Studies; Data; Dendritic Cells; Disease; Equilibrium; Frequencies; Functional disorder; Future; Hepatitis B Virus; Immune; Immune System Diseases; Immune response; In Vitro; Interferons; Interleukin-10; Literature; Liver diseases; Monitor; Natural Killer Cells; Outcome; Pathogenesis; Pathway interactions; Patients; Phenotype; Primary carcinoma of the liver cells; Publishing; Regulation; Regulatory Pathway; Regulatory T-Lymphocyte; Relative (related person); Risk; Shapes; Signal Transduction; T cell response; T-Lymphocyte; Therapeutic; Treatment outcome; Vaccines; Viral Antigens; Viremia; Virus; Virus Diseases; base; in vivo; insight; response

DESCRIPTION (provided by applicant): Hepatitis B virus (HBV) is a hepatotropic, enveloped, partially double-stranded DMA virus that causes acute and chronic hepatitis with progression to cirrhosis and hepatocellular carcinoma (HCC). Despite an effective vaccine, over 350 million people throughout the world are chronically infected with HBV and may be at risk for progressive liver disease without optimal antiviral therapy. While HBV clearance is associated with robust and broad virus-specific IFN(+ type 1 effector T cell responses, viremia persists with impaired virus-specific effector T cells that cannot clear viremia but may nonetheless contribute to disease pathogenesis. Based on published literature and our own preliminary data implicating immune regulatory (FoxP3+ Tregs, IL-10) and costimulatory (PD-1) pathways in chronic viral infections including HBV, we hypothesize that the outcome of HBV infection and therapy is defined by the balance between antiviral effector and regulatory T-cell responses that are further shaped by innate signals. We also propose that targeted inhibition of negative immune regulatory pathways may reverse the antiviral effector dysfunction and unmask the underlying effector capacity for prolonged virus control. To this end, we will examine the following 3 specific aims to determine if: 1) HBV persists with distinct effector and regulatory T-cell responses that can predict clinical and therapeutic outcomes; 2) Virus suppression during HBV therapy will enhance antiviral effector T-cell function and reduce inhibitory immune regulatory factors; 3) Modulation in adaptive immune responses with therapeutic HBV suppression is defined by innate immune response. The proposed studies will provide insights to the mechanisms of immune dysfunction in HBV persistence, define potential early immunological markers to prognosticate therapeutic outcome and to define future immune-based strategies to enhance long term therapeutic outcome.

描述（由申请人提供）：丙型肝炎病毒（HBV）是一种肝炎，包裹，部分双链DMA病毒，会导致急性和慢性肝炎，发展为肝硬化和肝细胞癌癌（HCC）。尽管有有效的疫苗，但全世界有超过3.5亿人患有HBV感染，并且可能有进行性肝脏疾病的风险，而无需最佳的抗病毒药疗法。虽然HBV清除率与鲁棒和广泛的病毒特异性IFN（+ 1型效应T细胞反应有关，但病毒血症仍与无法清除病毒血症的病毒特异性效应T细胞持续存在，但可能会导致疾病发病机理。病毒感染包括HBV，我们假设HBV感染和治疗的结果是由抗病毒效应器和调节性T细胞反应之间的平衡来定义的，这些反应进一步由先天信号塑造出来。将检查以下3个特定目的，以确定：1）HBV是否持续使用不同的效应子和调节性T细胞反应，可以预测临床和治疗结果； 2）HBV治疗期间的抑制病毒将增强抗病毒效应T细胞功能并降低抑制性免疫调节因素； 3）通过治疗性HBV抑制的适应性免疫反应调节是由先天免疫反应定义的。拟议的研究将为HBV持久性中免疫功能障碍的机制提供见解，定义潜在的早期免疫标志物来预测治疗结果，并定义未来的基于免疫的策略以增强长期治疗结果。