Mechanisms of effective innate immunity in HCV treatment

HCV 治疗中有效的先天免疫机制

• 批准号: 8376377
• 负责人: JAMES C RYAN
• 金额: $ 34.75万
• 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/8376377
• 关键词: Acute Hepatitis C; Affect; Americas; Antiviral Agents; Area; CD94 Antigen; Caring; Case-Control Studies; Cell surface; Cells; Chronic; Chronic Hepatitis C; Cytokine Network Pathway; Dendritic Cells; Drug Delivery Systems; Family; Generations; Genetic Polymorphism; HLA Antigens; Hepatitis C; Hepatitis C virus; Immune system; Individual; Instruction; Ligands; Liver; Liver Cirrhosis; Macrophage Activation; Malignant neoplasm of liver; Memory; Minority; Morbidity - disease rate; NK Cell Activation; Natural Immunity; Natural Killer Cells; Outcome; Pathway interactions; Patients; Phenotype; Prospective Studies; Proteins; Research; Specimen; Stress; T-Lymphocyte; Viral; Virus; adaptive immunity; cytokine; cytotoxicity; immunoglobulin receptor; liver biopsy; memory acquisition; monocyte; mortality; peripheral blood; receptor; response; success; treatment response

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）长期感染了全球估计的1.7亿人。急性HCV感染后，只有15-45％的个体自发解决该病毒。 HCV无关的清除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会诱导A 外周血单核细胞中的激活状态失调，并且来自异常活化的单核细胞的细胞因子可能会对树突状细胞不利地影响T细胞的启动。在初步研究中，我们表明NK细胞受体的杀手免疫球蛋白受体（KIR）家族的多态性及 人类白细胞抗原（HLA）I类配体是自发HCV清除率的主要宿主决定因素。急性HCV感染会触发涉及自然细胞毒性受体NKG2D的NK细胞活化途径； NKG2D的应力诱导的细胞表面配体在HcVactiped上表达 外周血单核细胞。我们假设NK细胞可以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促进来促进有效的T细胞启动。此外，我们提出，NK细胞的效应子和细胞因子反应可能部分是由NKG2D触发的，并通过抑制性和激活KIR进行调节，并且具有具有A的NK细胞。 “记忆”表型可能会导致自适应无动病毒反应。 在该项目中，我们将对在治疗引起的HCV消除的背景下对NK细胞受体谱，NK细胞效应子和记忆反应，单核细胞激活状态和细胞因子网络进行Mulfivariate分析。这些研究将使用回顾性病例对照研究中的患者的外周血和肝活检的标本以及对HCV感染标准护理治疗的反应的前瞻性研究。我们希望确定：（1）控制NK细胞Activatton的多态受体是否可以预测慢性HCV中的垂直病毒治疗反应的不同，以及记忆NK细胞的获取是否与消除病毒相关； （2）特定的NK单元和 单核细胞/巨噬细胞激活和细胞因子谱有助于成功治疗引起的HCV感染清除率。这些结果将与项目2中自适应免疫获得的结果一致分析。