Mechanisms of effective innate immunity in HCV treatment

HCV 治疗中有效的先天免疫机制

基本信息

批准号：
7919825
负责人：
JAMES C RYAN
金额：
$ 17.2万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-15 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7919825
关键词：
Acute Hepatitis C Address Affect Aftercare Americas Antigen Receptors Antigen-Presenting Cells Antiviral Agents Antiviral Therapy B-Lymphocytes CD80 gene CD94 Antigen Caring Case-Control Studies Cell Degranulation Cell surface Cells Chronic Chronic Hepatitis C Clinical Cytokine Network Pathway Cytolysis Data Dendritic Cells Down-Regulation Drug Delivery Systems Enrollment Exposure to Family Flow Cytometry Generations Genetic Genetic Polymorphism Genotype HLA Antigens Hepatitis C Hepatitis C virus Human Immune Immune response Immune system Immunity In Vitro Individual Inflammatory Instruction Interferon-alpha Ligands Liver Liver Cirrhosis Lymphocyte Macrophage Activation Malignant neoplasm of liver Memory Minority Morbidity - disease rate NK Cell Activation Natural Immunity Natural Killer Cells Outcome Pathway interactions Patients Pattern Peripheral Peripheral Blood Mononuclear Cell Phenotype Play Population Process Prospective Studies Proteins Publishing Role Serum Source Specimen Stress T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Time Treatment outcome Up-Regulation Viral Viral Antigens Virus Virus Diseases adaptive immunity anti-hepatitis C base chemokine clinical epidemiology cohort cytokine cytotoxic cytotoxicity hepatitis C virus nucleocapsid protein immunoglobulin receptor intrahepatic leukocyte antigen typing liver biopsy memory acquisition monocyte mortality peripheral blood prospective receptor receptor internalization research study response success treatment response

项目摘要

The hepatitis C virus (HCV) chronically infects an estimated 170 million people worldwide. Following acute HCV infectton, only 15-45% of individuals resolve the virus spontaneously. Clearance of HCV infecfion requires the generation of potent antiviral T cell effectors. Virally encoded proteins are known to induce a dysregulated activation state In peripheral blood monocytes, and cytokines from aberrantly activated monocytes can adversely affect T cell priming by dendritic cells. In preliminary studies, we have shown that polymorphisms of the Killer Immunoglobulin Receptor (KIR) family of NK cell receptors and their human leukocyte antigen (HLA) class I ligands are major host determinants of spontaneous HCV clearance; that acute HCV infection triggers NK cell activation pathways involving the natural cytotoxicity receptor NKG2D; and that stress-inducible cell-surface ligands for NKG2D are expressed on HCVactivated peripheral blood monocytes. We hypothesize that NK cells may promote effective T cell priming by clearing aberrantly-activated monocytes and virally infected cells, or by contribufing to the elaboration of potent antiviral cytokines. Moreover, we propose that effector and cytokine responses of NK cells may be triggered, in part, by NKG2D and modulated by inhibitory and activating KIR, and that NK cells with a "memory" phenotype may contribute direcfiy to adaptive anfiviral responses. In this Project, we will perform mulfivariate analysis of NK cell receptor profiles, NK cell effector and memory responses, monocyte activation states, and cytokine networks in the context of treatment-induced HCV eradication. These studies will be performed using specimens of peripheral blood and liver biopsies from patients in a retrospective case-control study and a prospective study of response to standard-of care treatment of HCV infection. We wish to determine: (1) whether polymorphic receptors controlling NK cell activatton predict divergent anfiviral treatment responses in chronic HCV and whether the acquisition of memory NK cells correlates with viral eradication; and (2) whether specific NK cell and monocyte/macrophage activation and cytokine profiles contribute to successful treatment-induced clearance of HCV infectton. These results will be analyzed in concert with those obtained on adaptive immunity in Project 2.

丙型肝炎病毒 (HCV) 长期感染全球约 1.7 亿人。急性 HCV 感染后，只有 15-45% 的人能自发消除病毒。清除 HCV 感染需要产生有效的抗病毒 T 细胞效应子。已知病毒编码的蛋白质可诱导失调的激活状态在外周血单核细胞中，异常激活的单核细胞产生的细胞因子会对树突状细胞的 T 细胞启动产生不利影响。在初步研究中，我们发现 NK 细胞受体的杀伤性免疫球蛋白受体 (KIR) 家族的多态性及其作用人类白细胞抗原 (HLA) I 类配体是自发 HCV 清除的主要宿主决定因素；急性 HCV 感染触发涉及天然细胞毒性受体 NKG2D 的 NK 细胞激活途径； NKG2D 的应激诱导细胞表面配体在 HCV 激活上表达外周血单核细胞。我们假设 NK 细胞可能通过清除异常激活的单核细胞和病毒感染的细胞，或通过促进有效的抗病毒细胞因子的产生来促进有效的 T 细胞启动。此外，我们认为 NK 细胞的效应子和细胞因子反应可能部分由 NKG2D 触发，并通过抑制性和激活性 KIR 进行调节，并且 NK 细胞具有 “记忆”表型可能直接有助于适应性抗病毒反应。在这个项目中，我们将对 NK 细胞受体谱、NK 细胞效应器和记忆反应、单核细胞激活状态以及治疗诱导 HCV 根除的细胞因子网络进行多变量分析。这些研究将使用来自患者的外周血和肝活检样本进行回顾性病例对照研究和对 HCV 感染标准护理治疗反应的前瞻性研究。我们希望确定：（1）控制 NK 细胞激活的多态性受体是否可以预测慢性 HCV 中不同的抗病毒治疗反应，以及记忆 NK 细胞的获得是否与病毒根除相关； (2) 是否有特定的 NK 细胞和单核细胞/巨噬细胞激活和细胞因子谱有助于成功治疗诱导的 HCV 感染清除。这些结果将与项目 2 中获得的适应性免疫结果相结合进行分析。