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Investigation of Novel Roles For IRF7 in EAE

IRF7 在 EAE 中的新作用研究

基本信息

批准号：
9301057
负责人：
DAVID N IRANI
金额：
$ 19.38万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9301057
关键词：
Adoptive Transfer Alpha Cell Animal Model Autoimmune Process B-Lymphocytes Brain CD4 Positive T Lymphocytes CNS Demyelinating Autoimmune Diseases 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 Pathogenicity 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 Structure Structure of germinal center of lymph node Symptoms Testing Therapeutic Therapeutic Effect Transcript Variant alternative treatment cell type chemokine disability experimental study in vivo interferon regulatory factor-7 multiple sclerosis patient multiple sclerosis treatment neutralizing antibody novel prevent response transcription factor treatment response

项目摘要

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.

项目总结/摘要内源性和外源性β-干扰素对实验性自身免疫性脑脊髓炎的抑制作用 (EAE)在小鼠和多发性硬化症（MS）在人类通过不明确的机制。尽管如此，IFN-β非- 可以在两种疾病中识别出应答者。转录因子IFN调节因子-7（IRF 7）是一个关键的体内I型IFN产生的调节剂。遗传数据将IRF基因多态性与MS联系起来，包括一例疾病相关变异与未能诱导多种已知干扰素相关的病例在IFN-β治疗开始后，我们发现IRF 7缺陷小鼠发育得更快，与野生型对照相比，EAE更严重，趋化因子、C-X-C基序趋化因子配体13 在基线和EAE期间的脊髓中，IRF 7缺陷小鼠中的CXCL 13（CXCL 13）异常高。先前的研究表明，CXCL 13维持髓鞘特异性CD 4 + T细胞应答和临床症状在疾病期间。综上所述，这些数据使我们假设IRF 7/I型干扰素抑制淋巴样细胞产生CXCL 13（或防止产生CXCL 13的淋巴样细胞的出现），适应机制，以限制致病性中枢神经系统炎症在EAE。我们将通过两个测试来验证我们的假设。具体目的：1）阐明IRF 7如何抑制致脑炎性Th 17细胞并抑制过继转移 EAE通过受体宿主中的作用，和2）为了证实IRF 7缺陷小鼠对EAE的易感性增加， EAE与CXCL 13的表达改变有因果关系，并研究CXCL 13如何维持EAE 严重性。我们的主要目的是进一步描述IRF 7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IRF 7和I型IFN的作用与淋巴趋化因子的产生联系起来。我们长期目标是更好地了解IFN-β在EAE和MS中的有效性，并开发方法，快速识别IFN-β无应答的MS患者，以便启动替代治疗毫不拖延IFN-β仍然是RRMS最常用的处方治疗，并将继续使用因此，了解它在这种疾病中的作用仍然是义不容辞的。