MOG-Specific T Cell Trafficking in the Central Nervous System

MOG 特异性 T 细胞在中枢神经系统中的运输

基本信息

批准号：
7560053
负责人：
Joan M Goverman
金额：
$ 43.73万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7560053
关键词：
Adoptive Transfer Animal Model Antigen-Presenting Cells Antigens Avidity Brain Candidate Disease Gene Cells Cellular Immunity Central Nervous System Diseases Clinical Demyelinations Dependence Encephalitis Encephalomyelitis Epitopes Exhibits Experimental Autoimmune Encephalomyelitis Flow Cytometry Immunization Immunochemistry Inflammation Inflammatory Inflammatory Infiltrate Inflammatory Response Interferons Interleukin-17 Lesion Mediating Modeling Molecular Multiple Sclerosis Mus Myelin Myelin Proteins Myelitis Neuraxis Patients Pattern Population Proliferating Recombinants Research Rodent Rodent Model Role Specificity Spinal Cord System T-Lymphocyte T-Lymphocyte Subsets Testing Th1 Cells Transgenic Model base central nervous system demyelinating disorder enzyme linked immunospot assay human disease in vitro activity in vivo migration mouse model oligodendrocyte-myelin glycoprotein response trafficking white matter

项目摘要

DESCRIPTION (provided by applicant): Project Summary Multiple sclerosis (MS) is a neuroinflammatory disease of the central nervous system. The diverse clinical signs seen in MS patients reflect the wide distribution of inflammatory infiltrates, demyelinating plaques and axonal damage in the white matter tracks of the brain and spinal cord. Experimental allergic encephalomyelitis (EAE) is an animal model of MS that is induced by stimulating T cell-mediated immunity to myelin antigens. EAE has many similarities to MS, including the presence of inflammatory infiltrates and demyelination in the white matter. Unlike MS, however, the lesions are restricted predominantly to the spinal cord with significantly less inflammation seen in the brain. Thus, most rodent EAE models are not amenable to investigate mechanisms for targeting inflammation to the brain as well as the spinal cord. We have developed a unique model of EAE that allows us to determine the basis for different patterns of inflammation in the CNS. C3HeB/Fej x C3H.SW F1 mice generate T cells specific for three epitopes of myelin oligodendrocyte glycoprotein (MOG): MOG97-114, MOG79-90 and MOG35-55. Adoptive transfer of MOG97-114-specific T cells induces inflammation predominantly in the brain and not the spinal cord, while transfer of MOG79-90 and MOG35-55-specific T cells induces inflammation localized in the spinal cord and not the brain. T cells specific for all three epitopes generate IL-17+ and IFN-3+ cells, however, the IL-17:IFN-3 ratio is significantly higher for MOG97-114-specific T cells. By manipulating Th17:Th1 ratios for each specificity, we demonstrate that the localization of inflammatory cells in the brain versus the spinal cord is regulated by the ratio, and not the absolute number or epitope specificity, of myelin-specific Th17 and Th1 cells. Interestingly, MOG97-114 specific T cells also exhibit a higher functional avidity for their antigen compared to either MOG79-90 or MOG35-55-specific T cells. We propose to test the hypotheses that 1) T cell functional avidity for antigen determines the Th17:Th1 ratio in the responding population, 2) Th17 and Th1 cells differ in their ability to either migrate to, survive in, and/or proliferate in the brain versus the spinal cord and 3) resident cells within the brain and spinal cord differ in their response to infiltrating T cell populations biased toward Th17 or Th1.Project Narrative In multiple sclerosis, inflammatory lesions are typically disseminated in the white matter of the brain and frequently the spinal cord; however, lesions in most rodent models of MS predominate in the spinal cord with little brain inflammation. We developed a unique mouse model in which mechanisms mediated by different types of pathogenic T cells will be defined that regulates brain versus spinal cord inflammation. A better understanding of how, where and why different T cell subsets initiate and sustain inflammation in the central nervous system is critical to predict the efficacy and consequences of manipulating the activity of these T cells in MS therapies.

描述（由申请人提供）：项目摘要多发性硬化症 (MS) 是一种中枢神经系统的神经炎症性疾病。多发性硬化症患者的不同临床症状反映了大脑和脊髓白质轨迹中炎症浸润、脱髓鞘斑块和轴突损伤的广泛分布。实验性过敏性脑脊髓炎 (EAE) 是一种多发性硬化症动物模型，通过刺激 T 细胞介导的髓磷脂抗原免疫而诱导。 EAE 与 MS 有许多相似之处，包括白质中存在炎症浸润和脱髓鞘。然而，与多发性硬化症不同的是，病变主要局限于脊髓，大脑中的炎症明显较少。因此，大多数啮齿动物 EAE 模型不适合研究针对大脑和脊髓炎症的机制。我们开发了一种独特的 EAE 模型，使我们能够确定中枢神经系统中不同炎症模式的基础。 C3HeB/Fej x C3H.SW F1 小鼠产生对髓磷脂少突胶质细胞糖蛋白 (MOG) 的三个表位具有特异性的 T 细胞：MOG97-114、MOG79-90 和 MOG35-55。 MOG97-114 特异性 T 细胞的过继转移主要在大脑而非脊髓中诱导炎症，而 MOG79-90 和 MOG35-55 特异性 T 细胞的转移则诱导局部于脊髓而非大脑的炎症。对所有三个表位具有特异性的 T 细胞会产生 IL-17+ 和 IFN-3+ 细胞，但是 MOG97-114 特异性 T 细胞的 IL-17:IFN-3 比率显着更高。通过操纵每种特异性的 Th17:Th1 比率，我们证明大脑与脊髓中炎症细胞的定位是由髓磷脂特异性 Th17 和 Th1 细胞的比率而不是绝对数量或表位特异性调节的。有趣的是，与 MOG79-90 或 MOG35-55 特异性 T 细胞相比，MOG97-114 特异性 T 细胞对其抗原也表现出更高的功能亲和力。我们建议测试以下假设：1) T 细胞对抗原的功能亲和力决定了应答群体中 Th17:Th1 的比例，2) Th17 和 Th1 细胞迁移、存活和/或增殖的能力不同。大脑与脊髓以及 3) 大脑和脊髓内的常驻细胞对偏向 Th17 或 Th1 的浸润 T 细胞群的反应不同。多发性硬化症的炎症病变通常播散在大脑白质中，并且经常播散在脊髓中；然而，大多数多发性硬化症啮齿动物模型的病变主要集中在脊髓，很少有脑部炎症。我们开发了一种独特的小鼠模型，其中将定义由不同类型的致病性 T 细胞介导的机制，以调节大脑与脊髓炎症。更好地了解不同 T 细胞亚群如何、在何处以及为何引发和维持中枢神经系统炎症对于预测在多发性硬化症治疗中操纵这些 T 细胞活性的功效和后果至关重要。