IL-22 in HBV pathogenesis

IL-22 在 HBV 发病机制中的作用

• 批准号: 7569274
• 负责人: MICHAEL ROBEK
• 金额: $ 21.15万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7569274
• 关键词: Acute; Adverse effects; Animals; Antiviral Response; CD8B1 gene; Cell Culture Techniques; Cessation of life; Chronic Hepatitis; Chronic Hepatitis B; Disease; Family; Gene Expression; Genes; Hepatitis B; Hepatitis B Virus; Hepatocyte; Immune response; Inflammation; Injury; Integration Host Factors; Interferons; Interleukin-10; Lead; Liver; Liver Cirrhosis; Mediating; Mus; Play; Primary carcinoma of the liver cells; Process; Property; Proteins; Role; Signal Transduction; Simian B disease; T-Lymphocyte; Tissues; Transduction Gene; Transgenic Mice; Viral Antigens; Virus; Virus Replication; antimicrobial; base; cytokine; improved; interleukin-22; mouse model; prevent; public health relevance; receptor; research study; response; viral resistance; virus pathogenesis

DESCRIPTION (provided by applicant): Infection with the hepatitis B virus (HBV) can lead to chronic hepatitis and hepatocellular carcinoma. Current therapies for chronic HBV infection are only moderately effective, and are limited by severe side effects and viral resistance. Thus, there remains a need for new therapies for this serious disease. The liver injury associated with HBV infection is primarily caused by the CD8 T cell response to the virus. The interferon (IFN)-3-mediated noncytopathic inhibition of HBV is an important component of the host innate immune response to the virus, as it reduces virus replication without damaging the infected hepatocytes. However, relatively little is known about how the immune response to HBV is regulated by other host cytokines. IFN-3 belongs to the class II 1-helical cytokine family, which also includes IFN-1/2, the IFN-related proteins (IL-28A/B, IL-29), and the IL-10 family cytokines (IL-10, 19, 20, 22, 24, and 26). The IL-22 receptor is expressed on hepatocytes, and this cytokine displays immunomodulatory and protective properties in the liver and other tissues. We will examine the hypothesis that IL-22 plays an important role in the innate and adaptive host immune responses to HBV. Our general approach will be to use cell culture and transgenic mouse models of HBV replication to study the influence of IL-22 on virus replication, cellular gene expression, and inflammation after viral antigen recognition in the liver. These experiments are important, as they may identify IL-22 as a new host factor that limits HBV persistence and disease. A complete understanding of these processes may also lead to improved cytokine-based therapies for chronic HBV, which would have the potential to prevent hepatocellular carcinoma. PUBLIC HEALTH RELEVANCE: Chronic hepatitis B virus (HBV) infection is associated with liver cirrhosis and hepatocellular carcinoma, and causes over a million deaths each year worldwide. We will examine the hypothesis that IL-22, a recently characterized IL-10-related cytokine, protects the liver from HBV- associated injury. A complete understanding of the role of this cytokine in the immune response to HBV may lead to improved therapies for chronic HBV.

描述（申请人提供）：乙型肝炎病毒（HBV）感染可导致慢性肝炎和肝细胞癌。目前针对慢性乙型肝炎病毒感染的治疗方法仅具有中等效果，并且受到严重副作用和病毒耐药性的限制。因此，仍然需要针对这种严重疾病的新疗法。与 HBV 感染相关的肝损伤主要是由 CD8 T 细胞对病毒的反应引起的。干扰素 (IFN)-3 介导的 HBV 非细胞病变抑制是宿主对病毒先天免疫反应的重要组成部分，因为它可以减少病毒复制而不损害受感染的肝细胞。然而，对于乙肝病毒的免疫反应是如何受其他宿主细胞因子调节的，人们知之甚少。 IFN-3属于II类1-螺旋细胞因子家族，该家族还包括IFN-1/2、IFN相关蛋白（IL-28A/B、IL-29）和IL-10家族细胞因子（IL-10）。 10、19、20、22、24 和 26）。 IL-22 受体在肝细胞上表达，这种细胞因子在肝脏和其他组织中显示出免疫调节和保护特性。我们将检验 IL-22 在宿主对 HBV 的先天性和适应性免疫反应中发挥重要作用的假设。我们的一般方法是使用细胞培养和 HBV 复制的转基因小鼠模型来研究 IL-22 对病毒复制、细胞基因表达和肝脏中病毒抗原识别后炎症的影响。这些实验很重要，因为它们可能将 IL-22 确定为限制 HBV 持续存在和疾病的新宿主因子。对这些过程的全面了解还可能导致改进基于细胞因子的慢性乙型肝炎疗法，这将有可能预防肝细胞癌。公共卫生相关性：慢性乙型肝炎病毒 (HBV) 感染与肝硬化和肝细胞癌相关，每年在全球造成超过一百万人死亡。我们将检验这样的假设：IL-22（一种最近鉴定的 IL-10 相关细胞因子）可以保护肝脏免受 HBV 相关损伤。全面了解这种细胞因子在乙型肝炎免疫反应中的作用可能会改善慢性乙型肝炎的治疗方法。