Th17 cells are a newly defined subset of helper T cells that orchestrate inflammatory responses. Accumulating evidence implicates Th17 cells in the pathogenesis of autoimmune diseases. Indirect evidence suggests that they are also important in the pathogenesis of multiple sclerosis (MS). However, there are no studies in man to confirm this hypothesis. Th17 cells are pathogenic in experimental autoimmune encephalomyelitis and we have shown that IL-27 suppresses Th17 cells and autoimmune inflammation. Furthermore, IFN-(3 an immunomodulatory treatment for MS, has been shown to suppress Th17 cells and autoimmune inflammation in mice, via upregulation of IL-27. Based on these observations, we hypothesize that Th17 cells play a pathogenic role in MS and can be suppressed by IFN-|3 and IL27.To test this hypothesis, we propose to 1) characterize Th17 cells in MS patients, 2) determine the effect of IL-27 on human Th17 cells, and 3) examine the role of IL-27 in the suppressive effect of IFN-p on Th17 cells. These studies should result in a better understanding of the role of Th17 cells in MS , elucidate a mechanism of action of IFN-P in this disease, and have the potential to introduce IL-27 as a therapeutic modality in human autoimmune inflammation.
These studies are relevant to the overall mission of the ACE which is to further our understanding of cellmediated autoimmunity. In particular, Th17 cells are a recently characterised cellular subset that have been implicated in a numer of autoimmune conditions. Thus, although our studies are focused on MS, the findings from this project will likely be relevant to a range of autoimmune conditions.
|Xie, Chong; Ciric, Bogoljub; Yu, Shuo et al. (2016) IL-12RÎ²2 has a protective role in relapsing-remitting experimental autoimmune encephalomyelitis. J Neuroimmunol 291:59-69|
|Rasouli, Javad; Ciric, Bogoljub; Imitola, Jaime et al. (2015) Expression of GM-CSF in T Cells Is Increased in Multiple Sclerosis and Suppressed by IFN-Î² Therapy. J Immunol 194:5085-93|
|Shao, Wen-Hai; Zhen, Yuxuan; Finkelman, Fred D et al. (2014) The Mertk receptor tyrosine kinase promotes T-B interaction stimulated by IgD B-cell receptor cross-linking. J Autoimmun 53:78-84|
|Fitzgerald, Denise C; Fonseca-Kelly, ZoÃ«; Cullimore, Melissa L et al. (2013) Independent and interdependent immunoregulatory effects of IL-27, IFN-Î², and IL-10 in the suppression of human Th17 cells and murine experimental autoimmune encephalomyelitis. J Immunol 190:3225-34|
|Zizzo, Gaetano; Guerrieri, Justus; Dittman, Lindsay M et al. (2013) Circulating levels of soluble MER in lupus reflect M2c activation of monocytes/macrophages, autoantibody specificities and disease activity. Arthritis Res Ther 15:R212|
|Zizzo, Gaetano; Cohen, Philip L (2013) IL-17 stimulates differentiation of human anti-inflammatory macrophages and phagocytosis of apoptotic neutrophils in response to IL-10 and glucocorticoids. J Immunol 190:5237-46|
|Chen, David R; Cohen, Philip L (2012) Living life without B cells: is repeated B-cell depletion a safe and effective long-term treatment plan for rheumatoid arthritis? Int J Clin Rheumtol 7:159-166|
|Zizzo, Gaetano; Hilliard, Brendan A; Monestier, Marc et al. (2012) Efficient clearance of early apoptotic cells by human macrophages requires M2c polarization and MerTK induction. J Immunol 189:3508-20|
|Singh, Namrata; Cohen, Philip L (2012) The T cell in Sjogren's syndrome: force majeure, not spectateur. J Autoimmun 39:229-33|
|Finkel, Richard S; Crawford, Thomas O; Swoboda, Kathryn J et al. (2012) Candidate proteins, metabolites and transcripts in the Biomarkers for Spinal Muscular Atrophy (BforSMA) clinical study. PLoS One 7:e35462|
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