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: 8911388
• 负责人: A.M. Rostami
• 金额: $ 34.11万
• 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/8911388
• 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; 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）是中枢神经系统（CNS）的自身免疫性疾病。 Th17细胞在EAE的发病机理中很重要，可以假设它们在MS中起着相似的作用。我们已经表明，GM-CSF在EAE中Th17细胞的脑生成性中起着至关重要的作用。 GM-CSF在MS发病机理中的作用尚未得到很好的研究，并且尚不清楚可以调节这种细胞因子的因素。我们的初步数据表明，MS患者的T细胞多于健康个体的T细胞产生GM-CSF，而IFN-B治疗可降低这种产生。根据其在EAE和我们的发现中的作用，我们假设GM-CSF在MS发病机理中起重要作用，并且通过IFN-B治疗抑制。为了检验该假设，我们提出了以下特定目的：目标1：表征T细胞在周围和MS病变中的T细胞产生的GM-CSF。 EAE中GM-CSF的相关细胞来源是髓磷脂特异性T细胞。在MS髓磷脂特异性中，T细胞可能也是GM-CSF的主要SOU，但迄今为止，尚无研究表征MS患者T细胞的产生。我们的初步数据表明，急性MS脑病变中的大多数CD4+和CD8+ T细胞表达GM-CSF。其他人则表明，复发过程中CSF的CSF中GM-CSF增加了。这些数据支持GM-CSF在MS中起致病作用的假设。我们将测试以下假设：MS中T细胞的GM-CSF产生增加。目标2：研究GM-CSF对小胶质细胞激活及其神经毒性的影响。我们的初步发现表明，MS病变中激活的小胶质细胞表达高水平的GM-CSF受体，该受体与T细胞一起产生GM-CSF，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MS的治疗方法，但其疾病调节机理仍然尚未完全理解。 IFN-B对GM-CSF产生的影响尚不清楚。我们的初步发现表明，IFN-B显着降低了T细胞的GM-CSF产生，为我们的假设提供了基础，即IFN-B抑制了T细胞在MS中抑制GM-CSF的产生。这种抑制可能被证明是预测IFN-B治疗在个别MS患者中有效性的生物标志物。