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

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。Th 17细胞在EAE的发病机制中是重要的，据推测，它们可能在MS中发挥类似的作用。我们已经表明，GM-CSF在EAE中Th 17细胞的致脑炎性中起着至关重要的作用。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可以调节这种细胞因子的因素尚不清楚。我们的初步数据显示，MS患者的T细胞比健康个体产生更多的GM-CSF，而IFN-b治疗减少了这种产生。基于GM-CSF在EAE中的作用和我们的研究结果，我们假设GM-CSF在MS发病机制中起重要作用，并且通过IFN-b治疗而被抑制。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细胞的GM-CSF产生。EAE中GM-CSF的相关细胞来源是髓鞘特异性T细胞。在MS中，髓磷脂特异性T细胞也可能是GM-CSF的主要来源，但迄今为止还没有研究表征MS患者中T细胞的产生。我们的初步数据显示，急性MS脑病变中的大多数CD 4+和CD 8 + T细胞表达GM-CSF。其他人已经表明，在复发期间MS患者的CSF中GM-CSF增加。这些数据支持GM-CSF在MS中起致病作用的假设。我们将检验MS中T细胞产生GM-CSF增加的假设。目的2：研究GM-CSF对小胶质细胞活化及其神经毒性的影响。我们的初步研究结果表明，激活的小胶质细胞在MS病变表达高水平的GM-CSF受体，这与T细胞产生的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：为了研究IFN-β对MS中GM-CSF产生的影响。IFN-β是MS的广泛使用的治疗方法，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细胞的GM-CSF的生产，提供了我们的假设，IFN-B抑制MS中T细胞的GM-CSF生产的基础。这种抑制可能被证明是一个生物标志物，用于预测IFN-B治疗MS患者的有效性。

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.