Multiple sclerosis and its animal model, EAE, were thought to be mediated by Th1 cells. Discovery of Th17 cells, a novel IL-17-producing Th lineage that exhibits strong pathogenicity, led to a new paradigm with Th17 cells being the main culprit in autoimmune CNS inflammation. Th17 cells can be pathogenic or non-pathogenic depending upon stimulation with specific cytokines. Mechanisms by which Th17 cells induce autoimmune inflammation in the CNS are not well established. The central hypothesis of this proposal is that Th17 cells exert their encephalitogenicity in EAE through the action of GM-CSF and IL-17A on CNS cells, and this effect is regulated by IL-27. To test this hypothesis, we propose the following specific aims:
Aim 1 : To investigate the role of GM-CSF in the pathogenicity of Th17 cells. TGF-?1+IL-6 treated Th17 cells are non-pathogenic and have suppressed GM-CSF production compared to highly pathogenic IL-23 treated counterparts. We hypothesize that GM-CSF is a key factor in the pathogenicity of Th17 cells.
Aim 2 : To determine the role of CNS resident cells in the encephalitogenic action of IL-17A in EAE. Astrocytes and microglia express IL-17 receptor. We hypothesize that CNS cell responsiveness to IL-17A plays an important role in the pathogenesis of EAE. This is important to know if therapies are to be designed to interfere with the action of IL-17A.
Aim 3 : To study the regulatory effect of IL-27 derived from CNS resident cells on Th17 cells in EAE. Mechanisms responsible for the control of Th17 mediated inflammation in the CNS are largely unknown. We hypothesize that IL-27 produced by intrinsic CNS cells regulates local inflammation by suppressing Th17 cells. The studies proposed here are the natural continuations of our previous work on the role of cytokines IL-12 and IL-23 in the pathogenesis of EAE. Data generated from this project will advance our understanding of the role of Th17 cells in EAE and could pave the way to the design of new therapies for CNS inflammatory demyelination.

Public Health Relevance

A new population of immune T cells, called Th-17 that produce, among other products, proteins called IL-17 (hence the name Th-17), and GM-CSF has recently been discovered to cause severe inflammation. This type of inflammatory response has been implicated in human diseases and animal models of disease including Multiple Sclerosis (MS) and Experimental Autoimmune Encephalomyelitis (EAE) respectively. This proposal will test the hypothesis that Th-17 cells drive the inflammation of the central nervous system (CNS) by secreting two inflammatory mediators, IL-17 and GM-CSF that act on CNS cells to initiate the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS046782-05A2
Application #
7591320
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
2003-09-30
Project End
2014-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
5
Fiscal Year
2009
Total Cost
$337,969
Indirect Cost
Name
Thomas Jefferson University
Department
Neurology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Xie, Chong; Ciric, Bogoljub; Yu, Shuo et al. (2016) IL-12R?2 has a protective role in relapsing-remitting experimental autoimmune encephalomyelitis. J Neuroimmunol 291:59-69
Ding, Xiaoli; Yan, Yaping; Li, Xing et al. (2015) Silencing IFN-? binding/signaling in astrocytes versus microglia leads to opposite effects on central nervous system autoimmunity. J Immunol 194:4251-64
Rostami, Abdolmohamad; Ciric, Bogoljub (2013) Role of Th17 cells in the pathogenesis of CNS inflammatory demyelination. J Neurol Sci 333:76-87
Fitzgerald, Denise C; Fonseca-Kelly, Zoƫ; Cullimore, Melissa L et al. (2013) Independent and interdependent immunoregulatory effects of IL-27, IFN-?, and IL-10 in the suppression of human Th17 cells and murine experimental autoimmune encephalomyelitis. J Immunol 190:3225-34
Zhou, Fang; Lauretti, Elisabetta; di Meco, Antonio et al. (2013) Intravenous transfer of apoptotic cell-treated dendritic cells leads to immune tolerance by blocking Th17 cell activity. Immunobiology 218:1069-76
Li, Hongmei; Gonnella, Patricia; Safavi, Farinaz et al. (2013) Low dose zymosan ameliorates both chronic and relapsing experimental autoimmune encephalomyelitis. J Neuroimmunol 254:28-38
Yan, Yaping; Ding, Xiaoli; Li, Ke et al. (2012) CNS-specific therapy for ongoing EAE by silencing IL-17 pathway in astrocytes. Mol Ther 20:1338-48
Zhou, Fang; Ciric, Bogoljub; Li, Hongmei et al. (2012) IL-10 deficiency blocks the ability of LPS to regulate expression of tolerance-related molecules on dendritic cells. Eur J Immunol 42:1449-58
Li, Hongmei; Nourbakhsh, Bardia; Cullimore, Melissa et al. (2011) IL-9 is important for T-cell activation and differentiation in autoimmune inflammation of the central nervous system. Eur J Immunol 41:2197-206
El-Behi, Mohamed; Ciric, Bogoljub; Dai, Hong et al. (2011) The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nat Immunol 12:568-75

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