IL-22 in HBV pathogenesis

描述(由申请人提供)：感染乙肝病毒可导致慢性肝炎和肝细胞癌。目前治疗慢性乙肝病毒感染的方法只是中等有效，而且受到严重副作用和病毒耐药性的限制。因此，仍然需要新的治疗方法来治疗这种严重的疾病。与乙肝病毒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-3介导的非细胞病变抑制是宿主对病毒的先天免疫反应的重要组成部分，因为它减少了病毒的复制，而不损害被感染的肝细胞。然而，关于其他宿主细胞因子如何调节对乙肝病毒的免疫反应，人们知之甚少。干扰素-3属于II类1-螺旋细胞因子家族，还包括干扰素-1/2、干扰素相关蛋白(IL-28A/B、IL-29)和IL-10家族细胞因子(IL-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具有免疫调节和保护作用。我们将检验这一假设，即IL-22在先天和获得性宿主对乙肝病毒的免疫反应中发挥重要作用。我们的一般方法将是利用细胞培养和转基因小鼠复制乙肝病毒的模型来研究IL-22对病毒复制、细胞基因表达和病毒抗原识别后肝脏炎症的影响。这些实验很重要，因为它们可能会确定IL-22是一种限制乙肝病毒持久性和疾病的新宿主因素。对这些过程的完全了解也可能导致基于细胞因子的慢性乙肝治疗的改进，这将有可能预防肝细胞癌。公共卫生相关性：慢性乙肝病毒(乙肝)感染与肝硬变和肝细胞癌有关，每年导致全球100多万人死亡。我们将检验一种假设，即IL-22，一种最近表征的IL-10相关细胞因子，保护肝脏免受乙肝病毒相关的损伤。完全了解这种细胞因子在乙肝免疫反应中的作用可能有助于改进慢性乙肝的治疗方法。

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.