HLA -Dependent Racial Differences in Immune Response in Chronic Hepatitis C Virus

丙型肝炎病毒(HCV)是非甲非乙型肝炎的病原体。丙型肝炎病毒现在是美国慢性肝病最常见的原因，并已超过酒精性肝病，成为北美肝移植最常见的适应症。据估计，在所有美国人中，有1.8%的人感染了非洲裔美国人(AA)中较高的比例。这种疾病的一个特点是有慢性感染的倾向，接触过这种疾病的人中有85%患有慢性感染。UTHSC孟菲斯丙型肝炎合作研究中心的成立是为了支持临床和基础研究，以了解丙型肝炎病毒感染的慢性病基础和临床感染患者的治疗反应。大孟菲斯地区的人口中有55%是再生障碍性贫血，其中有一个严重的慢性丙型肝炎病毒感染问题。众所周知，AA对联合治疗的不良应答率加剧了该地区慢性丙型肝炎的明显健康问题。该项目的主要研究目标 孟菲斯丙型肝炎合作研究中心和这项建议是为了了解为什么再生障碍性贫血更容易受到慢性感染，以及为什么他们对联合治疗的应答率只有非再生障碍性贫血患者的50%或更低。为项目1提出的这项研究源于有趣的初步结果，即慢性丙型肝炎和AA治疗反应差与人类白细胞抗原-DRB1*11等位基因的关系。在慢性感染的再生障碍性贫血中，该等位基因的遗传频率大约是中南部普通再生障碍性贫血人群中预期频率的三倍。然而，DRB1*13等位基因似乎与治疗成功相关。该中心的拟议研究计划包括 两个项目，一个管理核心和一个临床核心项目#1将确定与非再生障碍性贫血患者相比，人类白细胞抗原依赖的免疫调节和T细胞特异性如何影响再生障碍性贫血患者与非再生障碍性贫血患者相比对丙型肝炎病毒的免疫反应和治疗反应的差异。其目的是：1)确定与慢性丙型肝炎病毒感染相关的人类白细胞抗原和免疫反应的差异，以及AA和CAU患者对治疗的反应差异。2)确定与CAU相比，人类白细胞抗原II类依赖的免疫调节可限制或抑制慢性感染者的丙型肝炎免疫反应，并降低AA患者的治疗反应。3)确定呈现丙型肝炎病毒蛋白的DR11、DR13和DR15的T细胞表位。4)确定 比较慢性丙型肝炎患者外周血和肝脏中丙型肝炎病毒特异性T细胞的T细胞受体结构。

Hepatitis C virus (HCV) is the etiologic agent of non-A, non-B hepatitis. HCV is now the most common cause of chronic liver disease in the United States and has surpassed alcoholic liver disease as the most common indication for liver transplantation in North America. An estimated 1.8% of all Americans are infected with a higher percentage among African Americans (AA). A hallmark of the disease is its predilection to become chronic with up to 85% of those exposed having chronic infection. The UTHSC Memphis Hepatitis C Cooperative Research Center was established to support clinical and basic research to understand the basis for chronic disease in HCV infection and response to therapy in clinically infected patients. The population of the greater Memphis area is 55% AA within which there is a significant problem with chronic HCV infection. The well documented poor response rate of AA to combination therapy exacerbates the obvious health problem of chronic HCV in this region. The primary research goal of the Memphis Hepatitis C Cooperative Research Center and this proposal is to understand why AA are more susceptible to chronic infection and why their response rate to combination therapy is only 50% or less of that for non AA patients. The research proposed for Project #1 derives from intriguing preliminary results on the association of chronic hepatitis C and poor response to therapy in AA to HLA-DRB1*11 alleles. The frequency of inheritance of this allele among chronically infected AA is approximately three times the expected frequency among the general AA population in the Midsouth. DRB1 * 13 alleles, however, appear to be associated with successful responses to therapy. The proposed research program for the Center includes two projects, an administrative core, and a clinical core Project #1 will determine how HLA class dependent immune regulation and T cell specificities affect differences in immune responses to HCV and response to therapy in AA compared to non AA patients. The aims are 1) Determine HLA and immune response differences that correlate with chronic HCV infection and differences in response to therapy between AA and CAU patients. 2) Identify HLA class II-dependent immune regulation that limits or suppresses HCV immune responses in chronically infected individuals and reduces the response to therapy in AA compared to CAU. 3) Identify T cell peptide epitopes for DR11, DR13, and DR15 presented HCV proteins. 4) Determine and compare T Cell receptor structures for HCV-specific T cells in peripheral blood and liver of chronic hepatitis C patients.