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The parasitic helminth product ES-62 suppresses pathogenesis in collagen-induced arthritis by targeting the interleukin-17–producing cellular network at multiple sites

Pineda, Miguel and McGrath, Mairi and Smith, Pauline and Al-Riyami, Lamyaa and Rzepecka, Justyna and Gracie, Alastair and Harnett, William and Harnett, Margaret (2012) The parasitic helminth product ES-62 suppresses pathogenesis in collagen-induced arthritis by targeting the interleukin-17–producing cellular network at multiple sites. Arthritis and Rheumatism, 64 (10). 3168–3178. ISSN 0004-3591

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    Abstract

    Among many survival strategies, parasitic worms secrete molecules to modulate host immune responses. One such product, ES-62, is protective in the collagen-induced arthritis (CIA) model of rheumatoid arthritis. As IL-17 has been reported to play a pathological role in the development of rheumatoid arthritis, we investigated whether targeting of IL-17 may explain the protection afforded by ES-62 in the CIA model. DBA/1 mice progressively display arthritis following immunization with type-II collagen. The protective effects of ES-62 were assessed by determination of cytokine levels, flow cytometric analysis of relevant cellular populations and in situ analysis of joint inflammation. ES-62 was found to downregulate IL-17 responses in the CIA model. Firstly, it acts to inhibit priming and polarisation of IL-17 responses by targeting a complex IL-17-producing network, involving signalling between dendritic cells and γδ or CD4+ T cells. In addition, ES-62 directly targets Th17 cells by downregulating MyD88 expression to suppress responses mediated by IL-1 and TLR ligands. Moreover, ES-62 modulates migration of γδ T cells and this is reflected by direct suppression of CD44 upregulation and, as evidenced by in situ analysis, dramatically reduced levels of IL-17-producing cells, including lymphocytes, infiltrating the joint. Finally, there is strong suppression of IL-17 production by cells resident in the joint, such as osteoclasts within the bone areas. Such unique multi-site manipulation of the initiation and effector phases of the IL-17 inflammatory network could be exploited in the development of novel therapeutics for rheumatoid arthritis.

    Item type: Article
    ID code: 40348
    Keywords: ES-62, collagen induced arthritis, inflammation, IL-17, Pharmacy and materia medica
    Subjects: Medicine > Pharmacy and materia medica
    Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
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      Depositing user: Pure Administrator
      Date Deposited: 05 Jul 2012 13:30
      Last modified: 25 Jan 2013 07:24
      URI: http://strathprints.strath.ac.uk/id/eprint/40348

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