Mechanisms of effective adaptive immunity in HCV treatment

HCV 治疗中有效的适应性免疫机制

• 批准号: 8376379
• 负责人: JOSEPH M MCCUNE
• 金额: $ 34.14万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8376379
• 关键词: Acute; Address; Antigens; Antiviral Agents; Area; CD4 Positive T Lymphocytes; CD8B1 gene; Caring; Case-Control Studies; Cells; Cessation of life; Chronic Hepatitis C; Cirrhosis; Cytotoxic T-Lymphocytes; Data; Dioxygenases; Disabled Persons; Drug Delivery Systems; Frequencies; Goals; Hepatitis C; Hepatitis C virus; Immune; Immune response; Immune system; Immunity; Infection; Interferons; Link; Liver; Malignant neoplasm of liver; Mediating; Morbidity - disease rate; Natural Immunity; Natural Killer Cells; Outcome; Patients; Phenotype; Prospective Studies; Research; Ribavirin; Specimen; T cell response; T-Lymphocyte; United States; Vaccines; Virus; adaptive immunity; base; economic cost; improved; indoleamine; liver biopsy; mortality; neutralizing antibody; peripheral blood; prophylactic; research study; response; social; treatment response

Hepatitis C virus (HCV) infection is the leading cause of liver-related morbidity and mortality in the United States, with an increasing number of deaths due to HCV-associated cirrhosis and liver cancer predicted over the next two decades. Spontaneous clearance is the best outcome of infection, but this occurs in only approximately 15-45% of patients. The goal of this project is to determine the mechanisms of effective adaptive immunity in treatment-mediated clearance of HCV infection. It seems clear that adapfive responses, particulariy CD8* cytotoxic T lymphocyte (CTL) responses, are necessary but not sufficient for HCV clearance. Subjects who respond to antiviral treatment, for example, have a higher frequency of antiviral CTL than do non-responders, but pre-exisfing CTL are insufficient to clear chronic HCV infection. Furthermore, in acute infecfion, effective CTL responses cannot be established in the absence of CD4* T cell help. We speculate that the contributions of CD4* T cells, interferon-a (IFNa), and ribavirin to CDS* T cell responses are linked at the level of the antigen-presenfing cell (APC). We hypothesize that IFNa and ribavirin contribute to HCV clearance in part via an infiuence on the quality of adaptive immune responses that is mediated by effects on APCs and cells of the innate immune system, including NK cells (evaluated in Project 1). In the experiments of this project, this hypothesis will be addressed using specimens of peripheral blood and liver biopsies from pafients in a retrospecfive case-control study and a prospective study of response to standard-of-care treatment of HCV infection. We wish to determine whether a successful response to antiviral treatment for HCV infecfion is related to: (1) enhancement of the polyfuncfionality and maturafion phenotype of CD4'' and CD8* T cells; (2) improved DC function and decreased induction of T regulatory mechanisms (e.g., inducfion of T-regs, indoleamine-2,3-dioxygenase, PD-1, etc); and/ or (3) high titers of total anti-E1/E2 anfibodies or of neutralizing antibodies against HCV. Given the temporal relationship between these parameters and the response to treatment, we may be able to ascertain which are likely to be causal. Viewed in conjunction with the experiments of Project 2 (on innate immunity), we will also be able to better understand the interplay between innate and adaptive immunity in treatment response to HCV.

丙型肝炎病毒（HCV）感染是肝脏相关发病率和死亡率的主要原因 美国因 HCV 相关肝硬化和肝癌死亡人数不断增加 预测未来二十年。自发清除是感染的最佳结果，但这 仅约 15-45% 的患者会发生这种情况。该项目的目标是确定 治疗介导的 HCV 感染清除中有效适应性免疫的机制。它似乎 明确适应性反应，特别是 CD8* 细胞毒性 T 淋巴细胞 (CTL) 反应是必要的 但不足以清除 HCV。例如，对抗病毒治疗有反应的受试者有 抗病毒 CTL 的频率高于无反应者，但先前存在的 CTL 不足以清除 慢性丙型肝炎病毒感染。此外，在急性感染中，无法建立有效的 CTL 反应 缺乏 CD4* T 细胞的帮助。我们推测 CD4* T 细胞、干扰素-a 的贡献 (IFNa) 和利巴韦林对 CDS* T 细胞的反应在抗原呈递细胞水平上相关 （APC）。 我们假设 IFNa 和利巴韦林部分通过影响 HCV 的活性来促进 HCV 清除。 由对 APC 和先天细胞的影响介导的适应性免疫反应的质量 免疫系统，包括 NK 细胞（在项目 1 中评估）。在本项目的实验中， 将使用来自患者的外周血和肝活检样本来解决这一假设 回顾性病例对照研究和对标准护理治疗反应的前瞻性研究 丙肝病毒感染。我们希望确定 HCV 抗病毒治疗是否能成功缓解 感染与以下因素有关：(1) CD4'' 的多功能性和成熟表型增强， CD8* T 细胞； (2) 改善 DC 功能并减少 T 调节机制的诱导（例如， T-regs、吲哚胺-2,3-双加氧酶、PD-1等的诱导；和/或(3)高滴度的总抗E1/E2 抗HCV的抗体或中和抗体。考虑到这些之间的时间关系 参数和对治疗的反应，我们也许能够确定哪些可能是因果关系。 结合项目2（先天免疫）的实验来看，我们还能够 更好地了解先天免疫和适应性免疫在 HCV 治疗反应中的相互作用。