IL-22 in HBV pathogenesis

描述（由申请人提供）：乙型肝炎病毒（HBV）感染可导致慢性肝炎和肝细胞癌。目前治疗慢性HBV感染的方法只有中等效果，并且受到严重副作用和病毒耐药性的限制。因此，对这种严重疾病仍然需要新的治疗方法。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的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HBV的免疫应答是如何被其他宿主细胞因子调节的，我们知之甚少。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、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表现出免疫调节和保护特性。我们将研究IL-22在宿主对HBV的先天和适应性免疫应答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对肝脏中病毒复制、细胞基因表达和病毒抗原识别后炎症的影响。这些实验很重要，因为它们可能确定IL-22是限制HBV持久性和疾病的新宿主因子。对这些过程的全面了解也可能导致改进基于细胞因子的慢性HBV治疗，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，每年在全世界造成100多万人死亡。我们将研究IL-22（一种最近发现的与il -10相关的细胞因子）保护肝脏免受HBV相关损伤的假设。全面了解这种细胞因子在HBV免疫应答中的作用可能会改善慢性HBV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.