NK cells in CNS inflammation and autoimmunity

NK 细胞在中枢神经系统炎症和自身免疫中的作用

基本信息

批准号：
8072733
负责人：
FU-DONG SHI
金额：
$ 39.03万
依托单位：
ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
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：
2010-05-14 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8072733
关键词：
Acute Disseminated Encephalomyelitis Address Alzheimer&apos s Disease Animal Model Antigens Asses Attenuated Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity Biological Assay Biological Process Bioluminescence Brain Diseases C57BL/6 Mouse CD4 Positive T Lymphocytes CNS autoimmunity CX3CL1 gene Cell-Mediated Cytolysis Cells Central Nervous System Diseases Clinical Coculture Techniques Complex Data Demyelinations Development Disease Encephalomyelitis Epilepsy Experimental Autoimmune Encephalomyelitis Fractalkine Frequencies Generations Genetic Germ Lines Helper-Inducer T-Lymphocyte Home environment Homing Human IRF4 gene Image Analysis Immune response Immune system Infiltration Inflammation Inflammatory Inflammatory Response Injection of therapeutic agent Interleukin-17 Interleukin-2 Interleukin-6 Investigation KLRD1 gene Label Large granular lymphocyte Literature Lymphocyte Lymphocyte Subset Magnetic Resonance Imaging Maintenance Mediating Microglia Modeling Monoclonal Antibodies Mononuclear Multiple Sclerosis Mus Myelin Natural Killer Cells Neuraxis Neurologic Outcome Parkinson Disease Pathogenesis Pathology Peptides Peripheral Play Production Qa-1 Antigen Research Role STAT3 gene Stroke T-Lymphocyte Testing Therapeutic Therapeutic Intervention Transgenic Organisms Trauma attenuation base body system cell type chemokine chemokine receptor cytokine cytotoxicity design disease phenotype in vivo insight interest killings novel oligodendrocyte-myelin glycoprotein prevent public health relevance receptor research study response stem transcription factor

项目摘要

DESCRIPTION (provided by applicant): NK cells in CNS inflammation and autoimmunity Project Summary: Natural killer (NK) cells are large, granular lymphocytes that operate through cytolytic activity and cytokine secretion, and represent an important component of the innate immune system. Our group has long been interested in understanding the biological functions of NK cells in autoimmune diseases, particularly their role in inflammation and autoimmunity in the central nervous system (CNS) such as multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Preliminary data and relevant literature suggest that the initiation of MS/EAE may stem from the interplay between cells of the innate and adaptive immune systems, including NK cells. To test this possibility, we developed several cellular and genetic approaches to manipulate NK cells systemically and in the CNS, and investigated the capacity of these cells to impact the magnitude of CNS inflammation and autoimmunity to myelin antigens. We demonstrated that the systemic depletion of NK cells in all organ system using an anti-NK1.1 mAb, or selectively reduced the homing of NK cells to the CNS through a germ-line deletion of the chemokine receptor CX3CR1, leads to pronounced mononuclear lymphocyitic infiltration into the CNS, demyelination, and preferential expansion of CNS myelin- reactive Th17. Conversely, the expansion of NK cells via the engagement of the IL-2 receptor on NK cells significantly attenuated the CNS, but not peripheral Th17 cell responses. Further investigations revealed that NK cells reside in proximity to microglia in the CNS, and that can kill microglia. When NK cells were depleted or were unable to home to the CNS, microglia expanded and produced large amounts of Th17 polarizing cytokines. Also, the absence of NK cells promoted the activation of the Th17 lineage-specific transcription factors Rorc and STAT3 in a manner that was dependent on microglia. Based on these preliminary studies, we propose to dissect the cellular mechanism governing NK cell-mediated protection from EAE. Our central hypothesis is that NK cells control microglia in the inflamed CNS, and that NK cell/microglia interactions can inhibit myelin-reactive Th-17 cells and protect against CNS autoimmunity. To test this hypothesis, we will: 1) Dissect the interactions between NK cells and microglia in the CNS and identify the mechanism responsible for the cytolytic activity of NK cells against microglia; 2) Define the impact of NK cell/microglia interactions on the generation, maintenance and function of myelin-reactive CD4+ Th17 cells in the CNS; 3) Test NK-based therapeutic approaches for the protection from CNS inflammation and autoimmunity. PUBLIC HEALTH RELEVANCE: NK cells in CNS inflammation and autoimmunity Project Narrative: This study will elucidate key mechanisms by which natural killer (NK) cells can inhibit inflammation and autoimmunity in the central nervous system (CNS). The feasibility of NK-based therapeutic intervention in preventing CNS inflammation will be explored and the outcomes evaluated for possible implementation in the design of novel treatments for CNS inflammation and autoimmunity.

描述（由申请人提供）：中枢神经系统炎症和自身免疫中的 NK 细胞项目摘要：自然杀伤 (NK) 细胞是大型颗粒淋巴细胞，通过细胞溶解活性和细胞因子分泌发挥作用，代表先天免疫系统的重要组成部分。我们课题组长期以来对了解NK细胞在自身免疫性疾病中的生物学功能感兴趣，特别是它们在中枢神经系统（CNS）炎症和自身免疫中的作用，如多发性硬化症（MS）及其动物模型实验性自身免疫性脑脊髓炎（EAE）。初步数据和相关文献表明，MS/EAE 的发生可能源于先天免疫系统和适应性免疫系统细胞（包括 NK 细胞）之间的相互作用。为了测试这种可能性，我们开发了几种细胞和遗传方法来系统地和中枢神经系统中操纵 NK 细胞，并研究这些细胞影响中枢神经系统炎症程度和对髓磷脂抗原的自身免疫的能力。我们证明，使用抗 NK1.1 mAb 系统性地消耗所有器官系统中的 NK 细胞，或通过趋化因子受体 CX3CR1 的种系缺失选择性地减少 NK 细胞向中枢神经系统的归巢，会导致明显的单核淋巴细胞炎浸润中枢神经系统、脱髓鞘以及中枢神经系统髓磷脂反应性 Th17 的优先扩张。相反，通过 NK 细胞上的 IL-2 受体的结合而进行的 NK 细胞扩增显着减弱了 CNS，但不减弱外周 Th17 细胞的反应。进一步的研究表明，NK 细胞位于中枢神经系统中小胶质细胞附近，可以杀死小胶质细胞。当 NK 细胞耗尽或无法归巢至中枢神经系统时，小胶质细胞就会扩张并产生大量 Th17 极化细胞因子。此外，NK 细胞的缺失以依赖小胶质细胞的方式促进 Th17 谱系特异性转录因子 Rorc 和 STAT3 的激活。基于这些初步研究，我们建议剖析控制 NK 细胞介导的 EAE 保护的细胞机制。我们的中心假设是 NK 细胞控制发炎中枢神经系统中的小胶质细胞，并且 NK 细胞/小胶质细胞相互作用可以抑制髓磷脂反应性 Th-17 细胞并防止中枢神经系统自身免疫。为了验证这一假设，我们将： 1）剖析 NK 细胞和中枢神经系统小胶质细胞之间的相互作用，并确定 NK 细胞针对小胶质细胞的细胞溶解活性的机制； 2) 定义NK细胞/小胶质细胞相互作用对中枢神经系统中髓磷脂反应性CD4+ Th17细胞的生成、维持和功能的影响； 3) 测试基于 NK 的治疗方法，以预防中枢神经系统炎症和自身免疫。公共健康相关性：中枢神经系统炎症和自身免疫中的 NK 细胞项目叙述：这项研究将阐明自然杀伤 (NK) 细胞抑制中枢神经系统 (CNS) 炎症和自身免疫的关键机制。将探讨基于 NK 的治疗干预预防中枢神经系统炎症的可行性，并评估其结果，以便在中枢神经系统炎症和自身免疫的新型治疗设计中可能实施。