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

• 批准号: 8259450
• 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
• 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/8259450
• 关键词: Acute Disseminated Encephalomyelitis; Address; Alzheimer' 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

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）：CNS炎症和自身免疫中的NK细胞项目概述：自然杀伤（NK）细胞是通过细胞溶解活性和细胞因子分泌发挥作用的大颗粒淋巴细胞，是先天免疫系统的重要组成部分。本课题组长期以来一直致力于了解NK细胞在自身免疫性疾病中的生物学功能，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性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操纵NK细胞全身和中枢神经系统，并研究了这些细胞的能力，影响中枢神经系统炎症和自身免疫髓鞘抗原的程度。我们证明，使用抗NK1.1 mAb在所有器官系统中系统性消耗NK细胞，或通过趋化因子受体CX 3CR 1的种系缺失选择性减少NK细胞向CNS的归巢，导致明显的单核淋巴细胞浸润进入CNS、脱髓鞘和CNS髓鞘反应性Th 17的优先扩增。相反，通过NK细胞上的IL-2受体的参与的NK细胞的扩增显著减弱了CNS，但不是外周Th 17细胞应答。进一步的研究表明，NK细胞位于CNS中的小胶质细胞附近，并且可以杀死小胶质细胞。当NK细胞被耗尽或无法返回CNS时，小胶质细胞扩增并产生大量Th 17极化细胞因子。此外，NK细胞的缺乏促进了Th 17谱系特异性转录因子Rorc和STAT 3的激活，其方式依赖于小胶质细胞。基于这些初步的研究，我们建议解剖NK细胞介导的保护EAE的细胞机制。我们的中心假设是NK细胞控制发炎CNS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鞘反应性Th-17细胞并保护免受CNS自身免疫。为了验证这一假设，我们将：1）剖析中枢神经系统中NK细胞和小胶质细胞之间的相互作用，并确定NK细胞对小胶质细胞的细胞溶解活性的机制; 2）确定NK细胞/小胶质细胞相互作用对中枢神经系统中髓鞘反应性CD 4 + Th 17细胞的产生、维持和功能的影响; 3）测试基于NK的治疗方法以保护免于CNS炎症和自身免疫。 公共卫生关系：NK细胞在中枢神经系统炎症和自身免疫中的作用项目叙述：本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的治疗干预在预防CNS炎症中的可行性，并评估可能在CNS炎症和自身免疫的新型治疗设计中实施的结局。