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: 8640875
• 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 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8640875
• 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; 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; bioluminescence imaging; 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.

描述(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)细胞是一种大的颗粒状淋巴细胞，通过细胞溶解活动和细胞因子分泌来运作，是天然免疫系统的重要组成部分。长期以来，我们的研究小组一直有兴趣了解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的发生可能源于天然免疫系统细胞和获得性免疫系统细胞(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学方法来系统地和在中枢神经系统中操纵NK细胞，并研究了这些细胞影响中枢神经系统炎症和对髓鞘抗原的自身免疫的能力。我们证明，使用抗NK1.1单抗在所有器官系统中系统性地耗尽NK细胞，或者通过胚系缺失趋化因子受体CX3CR1选择性地减少NK细胞归巢到CNS，导致显著的单核淋巴细胞向CNS渗透，脱髓鞘，以及CNS髓鞘反应性Th17的优先扩张。相反，NK细胞通过与NK细胞上的IL-2受体结合而扩张，显著减弱了中枢神经系统的反应，但不能降低外周Th17细胞的反应。进一步的研究发现，NK细胞位于中枢神经系统的小胶质细胞附近，可以杀死小胶质细胞。当NK细胞耗尽或不能定位于中枢神经系统时，小胶质细胞扩张并产生大量Th17极化细胞因子。此外，NK细胞的缺失促进了Th17系特异性转录因子RORC和STAT3的激活，这种激活依赖于小胶质细胞。在这些初步研究的基础上，我们建议剖析NK细胞介导的EAE保护作用的细胞机制。我们的中心假设是，NK细胞控制着炎症CNS中的小胶质细胞，NK细胞/小胶质细胞的相互作用可以抑制髓鞘反应性Th-17细胞，保护CNS自身免疫。为了验证这一假说，我们将：1)剖析CNS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杀伤活性的机制；2)确定NK细胞和小胶质细胞相互作用对CNS中髓鞘反应性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，以保护CNS免受炎症和自身免疫的影响。

项目成果

Clinical significance of detection of antibodies to fetal and adult acetylcholine receptors in myasthenia gravis.

重症肌无力胎儿和成人乙酰胆碱受体抗体检测的临床意义

• DOI: 10.1007/s12264-012-1256-0
• 发表时间: 2012-10
• 期刊: NEUROSCIENCE BULLETIN
• 影响因子: 5.6
• 作者: Shi, Qi-Guang;Wang, Zhi-Hong;Ma, Xiao-Wei;Zhang, Da-Qi;Yang, Chun-Sheng;Shi, Fu-Dong;Yang, Li
• 通讯作者: Yang, Li

Roles of nicotinic acetylcholine receptors in stem cell survival/apoptosis, proliferation and differentiation.

• DOI: 10.2174/15665240113139990074
• 发表时间: 2013-10
• 期刊: Current molecular medicine
• 影响因子: 2.5
• 作者: J.‐X. Shen;D. Qin;H. Wang;C. Wu;F. Shi;J. Wu

Monocyte galactose/N-acetylgalactosamine-specific C-type lectin receptor stimulant immunotherapy of an experimental glioma. Part II: combination with external radiation improves survival.

• DOI: 10.2147/cmar.s33355
• 发表时间: 2012
• 期刊: Cancer management and research
• 影响因子: 3.3
• 作者: Kushchayev SV;Sankar T;Eggink LL;Kushchayeva YS;Wiener PC;Hoober JK;Eschbacher J;Liu R;Shi FD;Abdelwahab MG;Scheck AC;Preul MC
• 通讯作者: Preul MC

Combination of the Immune Modulator Fingolimod With Alteplase in Acute Ischemic Stroke: A Pilot Trial.

免疫调节剂芬戈莫德与阿替普酶联合治疗急性缺血性中风：初步试验。

• DOI: 10.1161/circulationaha.115.016371
• 发表时间: 2015-09-22
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Zhu Z;Fu Y;Tian D;Sun N;Han W;Chang G;Dong Y;Xu X;Liu Q;Huang D;Shi FD
• 通讯作者: Shi FD

Expansion of regulatory T cells via IL-2/anti-IL-2 mAb complexes suppresses experimental myasthenia.

• DOI: 10.1002/eji.200939792
• 发表时间: 2010-06
• 期刊: EUROPEAN JOURNAL OF IMMUNOLOGY
• 影响因子: 5.4
• 作者: Liu, Ruolan;Zhou, Qinghua;La Cava, Antonio;Campagnolo, Denise I.;Van Kaer, Luc;Shi, Fu-Dong
• 通讯作者: Shi, Fu-Dong