Progressive MS remains an untreatable form of the disease, and in order to intervene, a better understanding of the mechanisms by which infiltrating TEM cells of the adaptive immune system interface with glial cells is needed. Lymphoid follicles within the meninges and compartmentalized inflammation may be a major effector population for grey matter injury and incomplete remyelination, which renders axons susceptible to mitochondrial stress and calcium mediated degeneration. Alternatively, a low level of inflammation may be beneficial for promoting remyelination. To date, there is little information regarding how CNS infiltrating TEM subsets may differentially impact oligodendrocyte progenitor cells (OPCs) and remyelination, and the molecular pathways through which this occurs. Our preliminary data show that in vitro, IFN? suppresses OPC differentiation whereas, remarkably, IL-4 promotes OPC differentiation. In order to investigate the effects of T cells on remyelination in an in vivo model in which there is extensive remyelination, we have developed a novel model in which we adoptively transfer MOG reactive effector T cells (TEff) into mice with cuprizone induced demyelination (AT-cuprizone). In this system, adoptively transferred MOG reactive TEff markedly inhibited the endogenous remyelination that occurs after cessation of cuprizone feeding, without causing EAE. In order to probe the molecular signals that mediate the downstream effects of these cytokines, we have investigated several nuclear hormone receptor (NHR) family members including;thyroid hormone receptor (TR) and peroxisome proliferator activated receptor (PPAR). Ligation of PPAR? and TR?/? is known to enhance differentiation of OPC and induce (re)myelination, but how these NHRs are coordinately signaled and whether they can overcome the inhibitory effects of IFN? is unclear. We now show that IL-4 enhances PPAR? in OPCs, and this occurs in association with increased pSTAT6 and expression of the coactivator PGC1a in a heteromeric complex with TRb1. IFN? suppresses this pathway. We thus hypothesize that TEff cytokines mediate direct effects on OPCs by regulation of PPAR?through the canonical cytokine STAT signaling pathways known to modulate immune cells.

Public Health Relevance

Based on preliminary data, we hypothesize that T effector cytokines mediate direct effects on OPCs by regulation of PPAR? through the canonical cytokine STAT signaling pathways known to modulate immune cells. We will examine how CNS infiltrating T effector subsets may differentially impact oligodendrocyte progenitor cells (OPCs) and remyelination in vivo, and the molecular pathways through which this occurs. We will test combinations of drugs that both enhance developmental myelinating signaling pathways and can overcome the inhibitory effects of inflammation on remyelination.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37NS041435-13
Application #
8614318
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
2000-07-01
Project End
2017-08-30
Budget Start
2013-09-30
Budget End
2014-08-30
Support Year
13
Fiscal Year
2013
Total Cost
$405,000
Indirect Cost
$155,000
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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