Investigation of Novel Roles For IRF7 in EAE

IRF7 在 EAE 中的新作用研究

• 批准号: 9170834
• 负责人: DAVID N IRANI
• 金额: $ 23.25万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9170834
• 关键词: Adoptive Transfer; Animal Model; Autoimmune Process; B-Lymphocytes; Brain; CD4 Positive T Lymphocytes; CNS Demyelinating Autoimmune Diseases; CXC Chemokines; Cells; ChIP-seq; Chronic; Clinical; Clinical Trials; Data; Demyelinating Diseases; Disease; Dose; Experimental Autoimmune Encephalomyelitis; Failure; Family; Genes; Genetic; Genetic Polymorphism; Goals; Helper-Inducer T-Lymphocyte; Hematopoietic; Hour; Human; IRF1 gene; Immune; Individual; Inflammation; Inflammation Mediators; Injection of therapeutic agent; Interferon Type I; Interferon-beta; Interferons; Intrinsic factor; Investigation; Knockout Mice; Lead; Ligands; Ligation; Link; Lymphoid; Lymphoid Cell; MRI Scans; Mediating; Mediator of activation protein; Meninges; Methods; Multiple Sclerosis; Mus; Myelin; Neuraxis; Patients; Pattern recognition receptor; Peripheral Blood Mononuclear Cell; Predisposition; Production; Proteins; Recombinant Interferon Beta; Recruitment Activity; Relapse; Relapsing-Remitting Multiple Sclerosis; Reporter; Role; Serum; Severities; Source; Spinal Cord; Spinal Cord Lesions; Staging; Structure; Structure of germinal center of lymph node; Symptoms; T cell response; Testing; Therapeutic; Therapeutic Effect; Transcript; Variant; abstracting; alternative treatment; cell type; chemokine; disability; in vivo; interferon regulatory factor-7; multiple sclerosis patient; multiple sclerosis treatment; neutralizing antibody; novel; prevent; research study; response; transcription factor; treatment response

Project Summary/Abstract Both endogenous and exogenous interferon (IFN)-β suppress experimental autoimmune encephalomyelitis (EAE) in mice and multiple sclerosis (MS) in humans through poorly defined mechanisms. Still, IFN-β non- responders can be identified in both diseases. The transcription factor, IFN regulatory factor-7 (IRF7), is a key regulator of type-I IFN production in vivo. Genetic data have linked IRF gene polymorphisms with MS, including one case where the disease-associated variant correlated with a failure to induce multiple known IFN response genes following the initiation of IFN-β therapy. We find that IRF7-deficient mice develop more severe EAE than wild-type controls, and that levels of the chemokine, C-X-C motif chemokine ligand 13 (CXCL13), are abnormally high in IRF7-deficient mice both at baseline and in the spinal cord during EAE. Prior studies demonstrate that CXCL13 sustains myelin-specific CD4+ T cell responses and clinical symptoms during disease. Taken together, these data lead us to hypothesize that IRF7/type-I IFN acts to suppress lymphoid cell production of CXCL13 (or to prevent the emergence of CXCL13-producing lymphoid cells) as an adaptive mechanism to limit pathogenic CNS inflammation during EAE. We will test our hypothesis via two specific aims: 1) To clarify how IRF7 constrains encephalitogenic Th17 cells and suppresses adoptive transfer EAE via actions in the recipient host, and 2) To confirm the heightened susceptibility of IRF7-deficient mice to EAE is causally related to altered expression of CXCL13, and to investigate how CXCL13 acts to sustain EAE severity. Our main objective is to further characterize the role of IRF7 during CNS autoimmune demyelinating disease and to more directly link the actions of IRF7 and type-I IFN with lymphoid chemokine production. Our long-term goal is to better understand how IFN-β is efficacious in EAE and MS, and to develop methods to quickly identify MS patients who will be IFN-β non-responders so that alternative treatments can be initiated without delay. IFN-β remains the most commonly prescribed therapy for RRMS and will continue to be used for many years to come, so it remains incumbent to understand its actions in this disease.

项目概要/摘要 内源性和外源性干扰素 (IFN)-β 均可抑制实验性自身免疫性脑脊髓炎 小鼠中的 EAE（EAE）和人类中的多发性硬化症（MS）是通过不明确的机制实现的。尽管如此，IFN-β非 可以识别这两种疾病的反应者。转录因子 IFN 调节因子 7 (IRF7) 是关键 体内 I 型干扰素产生的调节剂。遗传数据已将 IRF 基因多态性与 MS 联系起来， 包括一个病例，其中疾病相关变异与未能诱导多种已知干扰素相关 IFN-β治疗开始后的反应基因。我们发现IRF7缺陷的小鼠发育得更好 比野生型对照严重的 EAE，并且趋化因子、C-X-C 基序趋化因子配体的水平 13 (CXCL13) 在 IRF7 缺陷小鼠中在基线和 EAE 期间的脊髓中均异常高。 先前的研究表明 CXCL13 维持髓磷脂特异性 CD4+ T 细胞反应和临床症状 患病期间。综上所述，这些数据使我们推测 IRF7/I 型 IFN 的作用是抑制 CXCL13 的淋巴细胞产生（或防止产生 CXCL13 的淋巴细胞的出现）作为 EAE 期间限制致病性 CNS 炎症的适应性机制。我们将通过两个方面来检验我们的假设 具体目标：1）阐明IRF7如何限制致脑炎性Th17细胞并抑制过继转移 通过受体宿主中的作用而发生 EAE，以及 2) 确认 IRF7 缺陷小鼠对 EAE 的易感性增加 EAE 与 CXCL13 表达的改变存在因果关系，并研究 CXCL13 如何发挥作用来维持 EAE 严重程度。我们的主要目标是进一步表征 IRF7 在中枢神经系统自身免疫性脱髓鞘过程中的作用 疾病，并更直接地将 IRF7 和 I 型 IFN 的作用与淋巴趋化因子的产生联系起来。我们的 长期目标是更好地了解 IFN-β 如何在 EAE 和 MS 中有效，并开发方法 快速识别对 IFN-β 无反应的多发性硬化症患者，以便开始替代治疗 毫不拖延。 IFN-β 仍然是 RRMS 最常用的处方疗法，并将继续使用 在未来的许多年里，因此我们仍然有责任了解其在这种疾病中的作用。