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

慢性丙型肝炎病毒免疫反应的 HLA 依赖性种族差异

• 批准号: 7475230
• 负责人: TONY N. MARION
• 金额: $ 21.42万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7475230
• 关键词: Address; Affect; African American; Alcoholic Liver Diseases; Alleles; American; Area; Basic Science; Biopsy Specimen; CD4 Positive T Lymphocytes; Chronic; Chronic Disease; Chronic Hepatitis C; Class; Clinical; Combined Modality Therapy; Disease; Epitopes; Frequencies; Goals; HLA-DRB1; Health; Hepatitis C; Hepatitis C virus; Immune; Immune response; Individual; Infection; Inherited; Liver; Liver diseases; North America; Patients; Peptides; Population; Proteins; Rate; Regulation; Research; Role; Structure; T-Cell Immunologic Specificity; T-Cell Receptor; T-Lymphocyte; Testing; Time; Tissues; United States; Viral Proteins; base; laser capture microdissection; liver transplantation; peripheral blood; programs; racial difference; research study; response; trend

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.

丙型肝炎病毒（HCV）是非甲非乙型肝炎的病原体。HCV现在是美国慢性肝病最常见的原因，并且已经超过酒精性肝病成为北美最常见的肝移植指征。据估计，所有美国人中有1.8%的人感染，非洲裔美国人（AA）的感染率更高。这种疾病的一个特点是它倾向于成为慢性的，高达85%的接触者患有慢性感染。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HCV感染慢性疾病的基础和临床感染患者对治疗的反应。大孟菲斯地区的人口是55%的AA，其中慢性HCV感染是一个重大问题。AA对联合治疗的不良反应率加剧了该地区慢性HCV的明显健康问题。的主要研究目标 孟菲斯丙型肝炎合作研究中心，这项建议是为了了解为什么AA更容易受到慢性感染，为什么他们对联合治疗的反应率只有非AA患者的50%或更少。项目#1的研究来自于关于慢性丙型肝炎和AA对HLA-DRB 1 *11等位基因治疗反应不良的相关性的有趣的初步结果。在慢性感染的AA中，该等位基因的遗传频率大约是中南地区一般AA人群预期频率的三倍。然而，DRB 1 * 13等位基因似乎与对治疗的成功反应相关。该中心的拟议研究计划包括 两个项目，管理核心和临床核心项目#1将确定HLA类依赖性免疫调节和T细胞特异性如何影响AA患者与非AA患者相比对HCV的免疫应答和对治疗的应答的差异。目的是1）确定与慢性HCV感染相关的HLA和免疫应答差异以及AA和CAU患者之间对治疗应答的差异。2)确定HLA II类依赖性免疫调节，限制或抑制慢性感染个体的HCV免疫应答，并降低AA与CAU相比对治疗的应答。3)鉴定DR 11、DR 13和DR 15呈递的HCV蛋白的T细胞肽表位。4)确定 并比较慢性丙型肝炎患者外周血和肝脏中HCV特异性T细胞的T细胞受体结构。