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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：
10461826
负责人：
STEFAN FESKE
金额：
$ 48.93万
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/10461826
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 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.

项目总结