The Role of GM-CSF in the Pathogenesis of Multiple Sclerosis

GM-CSF 在多发性硬化症发病机制中的作用

• 批准号: 8767198
• 负责人: A.M. Rostami
• 金额: $ 33.91万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8767198
• 关键词: Acute; Affect; Animal Model; Antigen-Presenting Cells; Autoimmune Diseases; Axon; Biological Markers; Brain; CD8B1 gene; Cells; Clinical Trials; Data; Development; Disease; Effectiveness; Effector Cell; Experimental Autoimmune Encephalomyelitis; Granulocyte-Macrophage Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor Receptors; Health; Human; Immune; Impairment; Individual; Inflammatory; Interferons; Lesion; Lymphoid Cell; Mediating; Mediator of activation protein; Microglia; Modeling; Multiple Sclerosis; Multiple Sclerosis Lesions; Myelin; Myeloid Cells; Nervous System Physiology; Neuraxis; Neurologic Deficit; Oligodendroglia; Pathogenesis; Pathogenicity; Patients; Peripheral; Phase; Play; Process; Production; Publishing; Relapse; Role; Source; T-Lymphocyte; Testing; Therapeutic; Tissues; base; cellular targeting; cytokine; gray matter; neurotoxicity; public health relevance; response; therapeutic target; white matter

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Th17 cells are important in the pathogenesis of EAE and it is hypothesized that they may play a similar role in MS. We have shown that GM-CSF plays an essential role in the encephalitogenicity of Th17 cells in EAE. The role of GM-CSF in the pathogenesis of MS has not been well studied, and the factors that can modulate this cytokine in health and disease are not known. Our preliminary data show that more T cells of MS patients produce GM-CSF than those of healthy individuals, and that IFN-b treatment reduces this production. Based on its role in EAE and our findings, we hypothesize that GM-CSF plays an important role in MS pathogenesis and is suppressed by treatment with IFN-b. To test this hypothesis we propose the following specific aims: Aim 1: To characterize GM-CSF production by T cells in the periphery and in MS lesions. The relevant cellular source of GM-CSF in EAE is myelin-specific T cells. It is likely that in MS myelin-specific T cells are also the principal souce of GM-CSF, but no study thus far has characterized its production by T cells in MS patients. Our preliminary data show that the majority of CD4+ and CD8+ T cells in acute MS brain lesions express GM-CSF. Others have shown that GM-CSF is increased in CSF of MS patients during relapse. These data support the hypothesis that GM-CSF plays a pathogenic role in MS. We will test the hypothesis that GM- CSF production by T cells is increased in MS. Aim 2: To investigate the effects of GM-CSF on microglial activation and their neurotoxicity. Our preliminary findings show that activated microglia in MS lesions express high levels of GM-CSF receptor, which, together with the production of GM-CSF by T cells, provides the basis for our hypothesis that GM-CSF mediates activation of microglia and promotes their neurotoxicity. Aim 3: To examine the effect of IFN-b on GM-CSF production in MS. IFN-b is a widely used treatment for MS, but its mechanism of disease modulation remains incompletely understood. The effect of IFN-b on GM-CSF production is unknown. Our preliminary findings show that IFN- b significantly reduces GM-CSF production by T cells, providing the basis for our hypothesis that IFN-b suppresses GM-CSF production by T cells in MS. This suppression may prove to be a biomarker for predicting the effectiveness of IFN-b therapy in individual MS patients.

描述（由申请人提供）：多发性硬化症（MS）是一种中枢神经系统（CNS）的自身免疫性疾病。 Th17 细胞在 EAE 的发病机制中很重要，并且推测它们可能在 MS 中发挥类似的作用。我们已经证明，GM-CSF 在 EAE 中 Th17 细胞的脑炎性中起着重要作用。 GM-CSF 在 MS 发病机制中的作用尚未得到充分研究，并且在健康和疾病中调节该细胞因子的因素尚不清楚。我们的初步数据表明，多发性硬化症患者的 T 细胞比健康个体产生更多的 GM-CSF，而 IFN-b 治疗会减少这种产生。根据其在 EAE 中的作用以及我们的研究结果，我们假设 GM-CSF 在 MS 发病机制中发挥重要作用，并可通过 IFN-b 治疗得到抑制。为了检验这一假设，我们提出以下具体目标： 目标 1：表征外周和 MS 病变中 T 细胞产生 GM-CSF 的特征。 EAE 中 GM-CSF 的相关细胞来源是髓磷脂特异性 T 细胞。在多发性硬化症中，髓磷脂特异性 T 细胞很可能也是 GM-CSF 的主要来源，但迄今为止还没有研究描述多发性硬化症患者中 T 细胞产生的 GM-CSF 的特征。我们的初步数据表明，急性 MS 脑损伤中的大多数 CD4+ 和 CD8+ T 细胞表达 GM-CSF。其他研究表明，多发性硬化症患者复发期间脑脊液中的 GM-CSF 增加。这些数据支持 GM-CSF 在 MS 中发挥致病作用的假设。我们将检验 MS 中 T 细胞产生的 GM-CSF 增加的假设。目标 2：研究 GM-CSF 对小胶质细胞激活的影响及其神经毒性。我们的初步研究结果表明，MS 病变中激活的小胶质细胞表达高水平的 GM-CSF 受体，这与 T 细胞产生 GM-CSF 一起，为我们的假设提供了基础，即 GM-CSF 介导小胶质细胞的激活并促进其神经毒性。目标 3：检查 IFN-b 对 MS 中 GM-CSF 产生的影响。 IFN-b 是一种广泛用于治疗多发性硬化症的药物，但其疾病调节机制仍不完全清楚。 IFN-b 对 GM-CSF 产生的影响尚不清楚。我们的初步研究结果表明，IFN-b 显着减少 T 细胞产生 GM-CSF，这为我们的假设提供了基础，即 IFN-b 抑制 MS 中 T 细胞产生 GM-CSF。这种抑制可能被证明是预测 IFN-b 治疗对个体 MS 患者有效性的生物标志物。