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

描述(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的发病机制中起重要作用，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细胞的脑原性中起重要作用。GM-CSF在MS发病机制中的作用尚未得到很好的研究，在健康和疾病中调节这种细胞因子的因素也不是很清楚。我们的初步数据显示，多发性硬化症患者的T细胞比健康人更多地产生GM-CSF，而干扰素-b治疗减少了这种产生。根据GM-CSF在EAE中的作用和我们的研究结果，我们推测GM-CSF在MS的发病机制中起重要作用，并被干扰素-b抑制。为了验证这一假设，我们提出了以下具体目标：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鞘特异性T细胞。在多发性硬化患者中，髓鞘特异性T细胞可能也是GM-CSF的主要来源，但到目前为止还没有研究确定其由多发性硬化症患者的T细胞产生。我们的初步数据显示，在MS急性脑部病变中，大多数CD4+和CD8+T细胞表达GM-CSF。另有研究表明，多发性硬化症患者复发时脑脊液中GM-CSF水平升高。这些数据支持GM-CSF在MS中起致病作用的假说。我们将检验在MS中T细胞产生GM-CSF增加的假说。目的2：探讨GM-CSF对小胶质细胞激活的影响及其神经毒性。我们的初步发现表明，MS病变中被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介导了小胶质细胞的激活并促进了其神经毒性。目的：探讨干扰素-b对多发性硬化患者GM-CSF产生的影响。干扰素-b是治疗多发性硬化症的常用药物，但其调控机制尚不完全清楚。干扰素-b对GM-CSF产生的影响尚不清楚。我们的初步发现表明，干扰素-b显著减少T细胞产生GM-CSF，为我们假设干扰素-b抑制多发性硬化症患者T细胞产生GM-CSF提供了依据。这种抑制作用可能被证明是预测干扰素-b治疗MS患者疗效的一个生物标志物。

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.