TARGETING INTERFERON LAMBDA SIGNALING DURING CENTRAL NERVOUS SYSTEM AUTOIMMUNITY

在中枢神经系统自身免疫期间靶向干扰素 Lambda 信号转导

• 批准号: 9758635
• 负责人: Sindhu Manivasagam
• 金额: $ 3.22万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-11 至 2021-03-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9758635
• 关键词: Acute; Address; Adoptive Transfer; Affect; Age of Onset; Animals; Antigen-Presenting Cells; Antiviral Agents; Autoimmune Diseases; Autoimmune Diseases of the Nervous System; Autoimmune Process; Autoimmunity; Automobile Driving; Axon; Binding; Biological Assay; CD80 gene; CNS autoimmunity; Cell Communication; Cells; Cerebrospinal Fluid; Chronic; Chronic Disease; Clinical; Coculture Techniques; Confocal Microscopy; Cues; Data; Demyelinating Diseases; Demyelinations; Development; Disease; Disease Progression; Endothelium; Enzyme-Linked Immunosorbent Assay; Exhibits; Experimental Autoimmune Encephalomyelitis; Fluorescence Microscopy; Frequencies; Goals; Human; Immune; Immune system; Immunohistochemistry; In Situ Hybridization; In Vitro; Infiltration; Inflammation; Inflammatory; Interferons; Lead; Lesion; Limb structure; Link; Lymphocyte; Maintenance; Measures; Mediating; Modeling; Multiple Sclerosis; Mus; Myelin; Myeloid Cells; Nature; Neuraxis; Neurologic Symptoms; Neurons; Onset of illness; Optic Neuritis; Pathogenicity; Pathologic; Patients; Peptides; Phenotype; Play; Population; Prevention; Production; Property; Protein Family; Recovery; Relapse; Reporter; Resolution; Role; Sampling; Secondary Lesion; Secondary Progressive Multiple Sclerosis; Secondary to; Serum; Severities; Signal Pathway; Signal Transduction; Source; Spinal Cord Lesions; T-Lymphocyte; Testing; Th1 Cells; Therapeutic; Tissues; Translating; Treatment Efficacy; United States; Viral; autoreactivity; axon injury; base; cytokine; disability; experimental study; immune activation; immunoregulation; improved; insight; lymphocyte proliferation; macrophage; member; monocyte; mouse model; multiple sclerosis patient; multiple sclerosis treatment; novel; novel therapeutic intervention; novel therapeutics; prevent; receptor; side effect; socioeconomics; spatiotemporal; young adult

Project Summary/Abstract The goal of this proposal is to elucidate the role of interferon lambda (IFNλ) during central nervous system (CNS) autoimmunity. The most common form of CNS autoimmunity among humans is multiple sclerosis (MS), a disease that affects over 2.5 million people worldwide2,16. MS is a demyelinating autoimmune disease that can cause a variety of neurologic symptoms including extremity weakness, optic neuritis, and ataxia1; it is a major cause of disability in young adults. Due to the young age of onset and continuously progressive nature of the disease, MS is not only a personal burden but also a substantial socioeconomic burden16. Currently, there are approximately one dozen therapeutic options for MS; although effective in reducing relapse frequency and severity, they have numerous side effects and none actually halt disease progression or promote recovery19. This suggests the need for an improved understanding of mechanisms driving chronic disease and to translate this information into new therapeutic strategies for MS. IFNλ (interferon lambda or type III IFN) is a class of cytokines closely related to type I IFN; both classes initiate analogous JAK STAT signaling pathways that induce expression of antiviral genes8-10. Type I IFN have been highly studied in CNS autoimmune diseases and play a protective role that is consistent with its use as a therapeutic for MS12,13,31. Very little, however, is known about the role of IFNλ in MS. Preliminary data has demonstrated that IFNλ may prevent recovery and lead to sustained inflammation in the murine model of CNS autoimmunity, experimental autoimmune encephalomyelitis (EAE). Animals deficient in IFNλ signaling demonstrated improved clinical scores, decreased inflammation, and decreased axonal damage during recovery from EAE. This suggests that IFNλ may play a critical role in disease maintenance after disease is already initiated. Therefore, the goal of this project is to understand how IFNλ modulates immune mediated inflammation and neuronal damage during CNS autoimmunity. The studies outlined in this proposal include experiments to analyze spatiotemporal expression of IFNλ and its receptor, to conditionally delete IFNλ receptor in a cell specific manner, to analyze in vitro cultures of antigen presenting cells (APCs) and T cells, to examine IFNλ’s effects on demyelination, and to measure IFNλ levels in MS patient samples. Completion of this project will provide insights into the cellular mechanisms underlying CNS autoimmune diseases.

项目摘要/摘要 该提案的目的是阐明中枢神经系统（CNS）中干扰素lambda（IFNλ）的作用 自身免疫性。人类中枢神经系统自身免疫的最常见形式是多发性硬化症（MS），一种疾病 这影响了全球超过250万人2,16人。 MS是一种脱髓鞘的自身免疫性疾病，可能导致 各种神经系统症状，包括肢体弱点，视神经神经毒素和ataxia1；这是主要原因 年轻人的残疾。由于发病年龄和疾病的持续进步性质，MS 不仅是个人伯恩尼（Burnen），而且是实质性的社会经济伯宁16。目前，大约有 MS的三十个治疗选择；尽管有效地降低继电器频率和严重程度，但它们具有 许多副作用，没有任何实际上停止疾病进展或促进康复19。这表明需要 为了改善对驱动慢性疾病的机制的理解，并将这些信息转化为新的 MS的治疗策略。 IFNλ（Interferon lambda或III型IFN）是与I型IFN密切相关的一类细胞因子；两个课程都启动 类似的JAK STAT信号通路，影响抗病毒基因的表达8-10。 I型IFN已经 CNS自身免疫性疾病中的高度研究二 MS12,13,31的治疗。然而，关于IFNλ在MS中的作用知之甚少。初步数据具有 证明IFNλ可能会阻止恢复并导致CNS鼠模型中的持续注射 自身免疫性，实验性自身免疫性脑脊髓炎（EAE）。动物缺乏IFNλ信号传导 表现出改善的临床评分，减少炎症和恢复过程中轴突损伤的增加 来自Eae。这表明IFNλ在疾病后可能在疾病维持中起关键作用 发起。因此，该项目的目的是了解IFNλ如何调节免疫介导 CNS自身免疫期间的炎症和神经元损伤。该提案中概述的研究包括 分析IFNλ及其受体的时空表达的实验，以有条件删除IFNλ受体 以细胞特异性的方式分析抗原呈递细胞（APC）和T细胞的体外培养物，以检查 IFNλ对脱髓鞘的影响，并测量MS患者样品中的IFNλ水平。该项目的完成 将提供有关中枢神经系统自身免疫性疾病的细胞机制的见解。