Inflammatory and Suppressive mechanisms of CNS autoimmunity

中枢神经系统自身免疫的炎症和抑制机制

基本信息

批准号：
8021831
负责人：
Eric S Huseby
金额：
$ 20.36万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8021831
关键词：
Abbreviations Adenoviruses Animal Model Antigen-Presenting Cells Attenuated Autoimmune Diseases Autoimmunity Biological Models Bone Marrow C57BL/6 Mouse CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene CNS autoimmunity Cell model Cell physiology Cells Central Nervous System Diseases Cessation of life Chronic Data Demyelinations Disease Epitopes Experimental Autoimmune Encephalomyelitis Future Genes Goals Grant Human Inflammatory Interleukin-10 Lesion Location MHC Class I Genes Mediating Modeling Multiple Sclerosis Multiple Sclerosis Lesions Mus Myelin Myelin Associated Glycoprotein Myelin Basic Proteins Myelin Proteins Neuraxis Neurologic Neurons Paralysed Pathogenesis Patients Proteins Proteolipids Protocols documentation Role Severity of illness Signal Transduction Symptoms T cell response T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Therapeutic Tissues Transgenic Organisms Vaccinia virus base cell type cellular targeting cytokine disease phenotype human disease in vivo insight macrophage migration novel oligodendrocyte-myelin glycoprotein public health relevance research study response

项目摘要

DESCRIPTION (provided by applicant): Multiple Sclerosis (MS) is an autoimmune disease that arises when self reactive T cells attack healthy cells of the Central Nervous System (CNS). One of the major goals of animal models is to identify candidate therapeutics for treating human disease. Because the suppressive effects of IL- 10 on T cells and macrophages, MS therapies based on IL-10 are very promising candidates. Using a novel animal model in which IL-10 signaling has been eliminated through a deletion of the IL-10R1 gene, we will identify how IL-10 limits CNS autoimmunity. A fundamental understanding of how this cytokine influence T cell responses and CNS autoimmunity is critical to our ability correctly target its suppressive effects. In addition, MS patients harbor both CD4 and CD8 T cells specific for CNS proteins. Although many experiments indicate a prominent role for CD8 T cells in several autoimmune diseases, there are very few models to study CD8 T cells in CNS disease. Because of this, how CD8 T cells induce CNS autoimmunity is poorly understood. We have identified several CD8 T cells reactive to CNS proteins and will use one of these responses to identify their cellular targets in vivo. A thorough understanding of how CNS-reactive CD8 T cells function should greatly enhance our ability to identify and develop additional disease attenuating protocols. PUBLIC HEALTH RELEVANCE: Narrative Multiple Sclerosis is an autoimmune disease mediated by T cells within the CNS. MS lesions contain both CD4 and CD8 T cells. Understanding how CD8 T cell contribute to CNS autoimmunity will give new insight into MS disease mechanisms and suggest candidate therapies to treat human autoimmune disease. Because the suppressive effects of IL-10 on T cells and macrophages, MS therapies based on IL-10 are very promising candidates. A fundamental understanding of how this cytokine influence T cell responses and CNS autoimmunity is critical to our ability correctly target its suppressive effects.

描述（由申请人提供）：多发性硬化症 (MS) 是一种自身免疫性疾病，当自身反应性 T 细胞攻击中枢神经系统 (CNS) 的健康细胞时就会出现这种疾病。动物模型的主要目标之一是确定治疗人类疾病的候选疗法。由于 IL-10 对 T 细胞和巨噬细胞的抑制作用，基于 IL-10 的 MS 疗法是非常有前途的候选者。使用一种新的动物模型，其中通过删除 IL-10R1 基因消除了 IL-10 信号传导，我们将确定 IL-10 如何限制 CNS 自身免疫。对这种细胞因子如何影响 T 细胞反应和中枢神经系统自身免疫的基本了解对于我们正确定位其抑制作用的能力至关重要。此外，多发性硬化症患者体内同时含有针对 CNS 蛋白的 CD4 和 CD8 T 细胞。尽管许多实验表明 CD8 T 细胞在多种自身免疫性疾病中发挥着重要作用，但研究 CD8 T 细胞在中枢神经系统疾病中的模型却很少。因此，人们对 CD8 T 细胞如何诱导 CNS 自身免疫知之甚少。我们已经鉴定出几种对 CNS 蛋白有反应的 CD8 T 细胞，并将使用其中一种反应来识别它们的体内细胞靶标。对中枢神经系统反应性 CD8 T 细胞如何发挥作用的彻底了解将大大增强我们识别和开发其他疾病减轻方案的能力。公共卫生相关性：叙述性多发性硬化症是一种由中枢神经系统内 T 细胞介导的自身免疫性疾病。 MS 病变同时含有 CD4 和 CD8 T 细胞。了解 CD8 T 细胞如何促进中枢神经系统自身免疫将为了解 MS 疾病机制提供新的见解，并提出治疗人类自身免疫性疾病的候选疗法。由于 IL-10 对 T 细胞和巨噬细胞的抑制作用，基于 IL-10 的 MS 疗法是非常有前途的候选者。对这种细胞因子如何影响 T 细胞反应和中枢神经系统自身免疫的基本了解对于我们正确定位其抑制作用的能力至关重要。