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Regulation of encephalitogenic T cells by CRAC channels

CRAC 通道对致脑炎 T 细胞的调节

基本信息

批准号：
10238856
负责人：
STEFAN FESKE
金额：
$ 48.87万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-14 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10238856
关键词：
Adverse effects Affect Animal Model Anti-Inflammatory Agents Attenuated Autoimmune Autoimmune Diseases Autoimmune Responses Bacterial Infections Benefits and Risks Brain CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CREB1 gene Calcineurin Calcium Calcium Channel Calcium ion Cell membrane Cell physiology Cells Cellular Immunity Complication Data Development Disease Disease Progression Dose Drug Targeting Enzymes Experimental Autoimmune Encephalomyelitis Functional disorder Gene Expression Genes Genetic Glycolysis Goals Granulocyte-Macrophage Colony-Stimulating Factor Helper-Inducer T-Lymphocyte Homologous Gene Human Immune Tolerance Immunity Immunotherapy Impairment In Vitro Infection Inflammation Inflammatory Response Interferon Type II Interleukin-17 Mediating Mediator of activation protein Metabolic Pathway Metabolism Molecular Multiple Sclerosis Multiple Sclerosis Lesions Mus Mutagenesis Mycoses Myelin Myelin Proteins Myelin Sheath Neuraxis Neurologic Symptoms Neurons Oxidative Phosphorylation Pathogenicity Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phosphotransferases Process Production Proteins Recurrent disease Regulation Regulatory T-Lymphocyte Relapse Risk Role STIM1 gene Safety Severities Severity of illness Spinal Cord Symptoms T-Lymphocyte T-Lymphocyte Subsets T-bet protein Testing Therapeutic Virus Diseases autoimmune inflammation autoreactive T cell autoreactivity brain cell chronic autoimmune disease cytokine efficacy evaluation in vivo inhibitor/antagonist interleukin-23 mouse model multiple sclerosis patient multiple sclerosis treatment novel strategies prevent transcription factor treatment strategy

项目摘要

Project Summary Multiple Sclerosis (MS) is an autoimmune disorder that is characterized by inflammation of the central nervous system (CNS) and localized destruction of the brain and spinal cord resulting in debilitating neurological symptoms. The disease processes underlying MS have been studied extensively in an animal model called experimental autoimmune encephalomyelitis (EAE), which greatly helped to develop several approved therapies for MS. In both MS and EAE, CD4+ helper T cells mistakenly recognize myelin protein expressed by brain cells as foreign and mount an autoimmune response against it. This inflammatory response is mediated mainly by two subsets of helper T cells, so-called Th1 and Th17 cells, which infiltrate the CNS and produce the proinflammatory cytokines IFNγ and IL-17, respectively. Interfering with the development of naive CD4+ T cells into Th1 and Th17 cells by genetic deletion of the transcription factors T-bet and RORγt, respectively, protects mice from EAE. Our lab showed that CD4+ T cells require the influx of calcium ions for their activation and ability to produce IFNγ and IL-17. Calcium influx is mediated by CRAC (calcium release-activated calcium) channels that are located in the plasma membrane of cells and formed by ORAI1 proteins. ORAI1 is activated by two intracellular proteins, STIM1 and STIM2, and deletion or mutagenesis of either of these three proteins attenuates CRAC channel function and calcium influx. Using mice with genetic deletion of ORAI1, STIM1 and STIM2 as well as specific CRAC channel inhibitors, we found that Th1 and Th17 cells are more dependent on calcium influx than other T cells for their function and ability to cause autoimmune inflammation. Treatment of T cells of mice or humans with a specific CRAC channel inhibitor reduced the production of IL-17 and IFNγ but did not affect T regulatory (Treg) cells. in a dose dependent manner. By genetically ablating either ORAI1, STIM1 or STIM2 in T cells, we could prevent or ameliorate the development of EAE and CNS inflammation in mice. Importantly, deletion of ORAI1 or STIM1 in T cells after EAE symptoms had already developed stopped the progression of disease. Similarly, treatment of mice in which EAE had developed with a CRAC channel inhibitor also significantly reduced disease severity without apparent adverse effects. These data suggest that calcium influx is an essential mediator of CNS inflammation in EAE and that its inhibition may be a new option for the treatment of MS. Drugs inhibiting CRAC channels have been developed, but have not been tested for their efficacy and safety in the treatment of MS and other T cell mediated autoimmune diseases. The goals of this application are twofold: (1) To understand the molecular mechanisms by which calcium influx via CRAC channels controls the development of CD4 T cells into pathogenic T cells, in particular Th1 and Th17 cells, that mediate CNS inflammation and EAE/MS. (2) To evaluate CRAC channels as drug targets for immunotherapy of EAE and eventually MS by studying their role in human T cells, in a mouse model of relapsing-remitting EAE and in immunity to infections as a potential complication of antiinflammatory therapy.

项目摘要多发性硬化症（MS）是一种以中枢神经系统炎症为特征的自身免疫性疾病，中枢神经系统（CNS）和脑和脊髓的局部破坏导致神经衰弱症状MS潜在的疾病过程已经在一种称为MS的动物模型中进行了广泛研究。实验性自身免疫性脑脊髓炎（EAE），这极大地帮助开发了几个批准的在MS和EAE中，CD 4+辅助性T细胞错误地识别MS表达的髓鞘蛋白，脑细胞作为外来物并对其产生自身免疫反应。这种炎症反应是由主要是通过两个辅助性T细胞亚群，即所谓的Th 1和Th 17细胞，它们浸润CNS并产生免疫应答。促炎细胞因子IFNγ和IL-17。干扰初始CD 4 + T细胞的发育分别通过基因缺失转录因子T-bet和RORγt进入Th 1和Th 17细胞， EAE小鼠。我们的实验室表明，CD 4 + T细胞需要钙离子的流入来激活，产生IFNγ和IL-17的能力。钙内流由CRAC（钙释放激活钙）介导位于细胞质膜中并由ORAI 1蛋白形成的通道。ORAI 1激活通过两种细胞内蛋白质，STIM 1和STIM 2，以及这三种蛋白质中的任一种的缺失或诱变，减弱CRAC通道功能和钙内流。使用基因缺失ORAI 1、STIM 1和 STIM 2以及特异性CRAC通道抑制剂，我们发现Th 1和Th 17细胞更依赖于钙内流比其他T细胞的功能和能力，导致自身免疫性炎症。治疗T 具有特异性CRAC通道抑制剂的小鼠或人的细胞减少了IL-17和IFNγ的产生，不影响调节性T细胞（Treg）。以剂量依赖的方式。通过基因切除ORAI 1，通过在T细胞中表达STIM 1或STIM 2，我们可以预防或改善EAE和CNS炎症的发展。小鼠重要的是，EAE症状发生后T细胞中的ORAI 1或STIM 1缺失已经停止疾病的发展类似地，用CRAC通道治疗已经发展EAE的小鼠，抑制剂还显著降低疾病严重程度而没有明显的副作用。这些数据表明钙离子内流是EAE中枢神经系统炎症的重要介质，抑制钙离子内流可能是EAE治疗的新选择已经开发了抑制CRAC通道的药物，但尚未测试用于MS的治疗。它们在治疗MS和其它T细胞介导的自身免疫性疾病中的功效和安全性。的目标这一应用是双重的：（1）了解钙通过CRAC流入的分子机制通道控制CD 4 T细胞发育成致病性T细胞，特别是Th 1和Th 17细胞，（2）评价CRAC通道作为免疫治疗药物靶点的可能性在复发缓解型EAE小鼠模型中，通过研究它们在人类T细胞中的作用，以及对作为化疗潜在并发症的感染的免疫力。