The role of CXCR3 chemokines in hepatitis C and other forms of viral hepatitis

大多数感染丙型肝炎病毒（HCV）的个体在10-20年的时间内表现出肝脏疾病的缓慢进展。这种肝脏疾病主要是宿主对感染HCV的肝细胞（肝细胞）的免疫应答的结果。作为这种免疫反应的一部分，浸润肝脏的免疫细胞数量增加。到目前为止，我们还不完全了解吸引这些细胞到肝脏的机制，但一类称为趋化因子的分子是最有可能的候选者。因此，更好地了解肝脏中表达的趋化因子，它们的调节以及在HCV相关肝病中吸引免疫细胞至肝脏的作用将有助于我们了解肝病的基本机制，并可能开发新的治疗策略。在初步研究中，我们已经表明，趋化因子干扰素诱导的T细胞α趋化因子（I-TAC）在感染HCV的人的肝脏中显着增加。I-TAC是CXCR 3配体趋化因子家族的成员，其将淋巴细胞吸引到炎症部位，因此可能在丙型肝炎中发挥重要作用。我们还表明，肝细胞表达I-TAC和HCV可以上调I-TAC的表达在HCV复制的实验室模型。该提案计划确定响应HCV复制的I-TAC表达的分子机制，并调查I-TAC表达是否是丙型肝炎特有的或肝脏病毒感染的一般特征。我们还计划通过使用CXCR 3配体拮抗剂来确定I-TAC和其他CXCR 3配体家族成员在病毒性肝炎小鼠模型中的作用。这些实验将增强或了解CXCR 3配体在丙型肝炎和病毒性肝炎中的作用。

The majority of individuals infected with hepatitis C virus (HCV) show a slow progression of liver disease over a period of 10-20 years. This liver disease is primarily a result of the host immune response to liver cells (hepatocytes) infected with HCV. As part of this immune response there in an increase in the number of immune cells that infiltrate the liver. To date we do not fully understand the mechanims that attract these cells to the liver but a class of molecules called chemokines is the most likely candidate. Thus a greater understanding of the chemokines expressed in the liver, their modulation and role in attracting immune cells to the liver in HCV-related liver disease will help us understand the basic mechanisms of liver disease with the possibility of development of novel therapeutic strategies. In pilot studies we have shown that the chemokine interferon-inducible T cell alpha chemoattractant (I-TAC) is significantly increased in the liver of persons infected with HCV. I-TAC is a member of the CXCR3 ligand chemokine family that attracts lymphocytes to sites of inflammation and as such may play an important role in hepatitis C. We have also shown that hepatocytes express I-TAC and that HCV can upregulate expression of I-TAC in a laboratory model of HCV replication. This proposal plans to determine the molecular mechanisms of I-TAC expression in response to HCV replication and to investigate if I-TAC expression is unique for hepatits C or a general feature of viral infections of the liver. We also plan to determine the the role of I-TAC and other CXCR3 ligand family members in a mouse model of viral hepatitis through the use of CXCR3 ligand antagonists. These experiments will enhance or knowledge of the role of the CXCR3 ligands in hepatitis C and viral hepatitis in general.