NK cell responses to JC polyomavirus

NK 细胞对 JC 多瘤病毒的反应

• 批准号: 10816656
• 负责人: Stephanie Jost
• 金额: $ 30.52万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10816656
• 关键词: Adult; Antibodies; Antibody-Dependent Enhancement; Antigens; Antiviral Response; Autoimmune Diseases; Autologous; Brain; Cell physiology; Cells; Clinical; Cloning; Cytomegalovirus; Data; Development; Diagnosis; Disease; Effector Cell; Endowment; Epitopes; Exhibits; Future; Gene Expression Profile; HIV; HIV Seropositivity; Hepatitis C virus; Herpesviridae Infections; Human; Immune; Immune Targeting; Immune response; Immune system; Immunocompromised Host; Immunologic Deficiency Syndromes; Immunotherapeutic agent; Immunotherapy; Impairment; Individual; Innate Immune System; Intervention; Investigation; JC Virus; Knowledge; Life; Ligands; Mediating; Memory; Morbidity - disease rate; Natural Killer Cells; Neoplasms; Onset of illness; Outcome; Outcome Study; Pathogenesis; Patients; Peptides; Persons; Phenotype; Play; Progressive Disease; Progressive Multifocal Leukoencephalopathy; Property; Reporting; Role; Sampling; Survivors; Testing; Time; Viral; Viral Load result; Viral Physiology; Virus; Virus Diseases; Work; antibody-dependent cell cytotoxicity; cytokine; cytotoxic; effective therapy; immune function; influenzavirus; innovation; mortality; mouse model; multiple sclerosis patient; new therapeutic target; novel; prevent; protective efficacy; receptor; response; sensitizing antigen

Most healthy individuals are persistently infected with the human polyomavirus JC (JCPyV) without significant consequences, yet in immunocompromised hosts, JCPyV can cause an often fatal disease -- progressive multifocal leukoencephalopathy (PML). There is currently no effective treatment to prevent or treat PML and novel immune-based therapies are urgently needed to decrease the morbidity and mortality associated with PML. Classically, natural killer (NK) cells are viewed as nonspecific effector cells of the innate immune system that play critical roles in defense against viral infections. Unexpectedly, it was recently demonstrated that besides their ability to rapidly eliminate virus-infected cells without the need for prior antigen sensitization, NK cells also exhibit adaptive immune functions. Different forms of adaptive capabilities have been identified among human NK cell subpopulations, including reports of true antigen-specific memory NK cells as well as adaptive NK cells with enhanced antibody-dependent functions. Adaptive NK cell subsets are endowed with potent anti-viral properties and protection mediated by virus-specific memory NK cells has been demonstrated in mouse models. Importantly, increasing evidence suggest that NK cell can mediate anti-viral responses to JCPyV. In particular, our preliminary data now show potent responses to JCPyV peptides by NK cells, isolation and cloning of single JCPyV-specific NK cells, and reduced JCPyV-specific antibody-dependent cellular cytotoxicity in PML patients. Based on these data, we hypothesize that NK cells and antibodies eliciting NK cell responses play a role in JCPyV pathogenesis. Specifically, we propose to build on our preliminary data to investigate the overarching hypothesis that specific subsets of NK cells can mediate potent anti-viral responses against JCPyV and protect immunocompromised patients against PML, through two focused independent Aims: (i) Define mechanisms crucial to control of JCPyV by NK cells; and (ii) Evaluate the role played by JCPyV-specific antibodies in modulating NK cell activity against JCPyV. If successful, the results of these innovative studies will contribute new knowledge of human immune response against JCPyV and provide the rationale to develop novel immunotherapeutic approaches to harness NK cell function against JCPyV.

大多数健康个体持续感染人多瘤病毒JC（JCPyV），而没有显著性差异。 然而，在免疫功能低下的宿主中，JCPyV可以引起一种通常致命的疾病-进行性 多灶性白质脑病（PML）。目前没有有效的治疗方法来预防或治疗PML， 迫切需要新的基于免疫的疗法来降低与 PML。传统上，自然杀伤（NK）细胞被视为先天免疫系统的非特异性效应细胞 在防御病毒感染中起着关键作用。出乎意料的是，最近的研究表明，除了 NK细胞具有快速消除病毒感染细胞而无需预先抗原致敏的能力， 表现出适应性免疫功能。不同形式的适应能力已被确定在人类 NK细胞亚群，包括真实抗原特异性记忆NK细胞以及适应性NK细胞的报告 具有增强的抗体依赖性功能。适应性NK细胞亚群被赋予有效的抗病毒 已经在小鼠模型中证实了由病毒特异性记忆NK细胞介导的免疫特性和保护作用。 重要的是，越来越多的证据表明NK细胞可以介导对JCPyV的抗病毒应答。特别是， 我们的初步数据现在显示NK细胞对JCPyV肽的有效应答，分离和克隆了单个 JCPyV特异性NK细胞，并降低PML患者中JCPyV特异性抗体依赖性细胞毒性。 基于这些数据，我们假设NK细胞和引发NK细胞应答的抗体在 JCPyV发病机制。具体来说，我们建议建立在我们的初步数据调查的总体 假设NK细胞的特定亚群可以介导针对JCPyV的有效抗病毒应答， 保护免疫功能低下的患者免受PML，通过两个集中的独立目标：（i）定义 NK细胞控制JCPyV的关键机制;和（ii）评估JCPyV特异性免疫应答所起的作用。 抗体调节NK细胞对JCPyV的活性。如果成功，这些创新研究的结果 将为人类对JCPyV的免疫应答提供新的知识，并为开发 利用NK细胞功能对抗JCPyV的新免疫方法。