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.

Public Health Relevance

It is believed that the cytokine GM-CSF plays an important role in multiple sclerosis (MS), which makes it an attractive therapeutic target, but relevant data are lacking. The proposed studies on GM-CSF are important for understanding its role in MS and the mechanisms underlying its actions. In addition, studies on IFN-b and GM-CSF will add to our understanding of the therapeutic mechanisms of IFN-b, the most widely used treatment for MS.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Utz, Ursula
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Thomas Jefferson University
Schools of Medicine
United States
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