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.
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.
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