Pineda, M.A. , McGrath, M.A., Smith, P.C., Al-Riyami, L., Rzepecka, J., Gracie, J.A., Harnett, W. and Harnett, M.M. (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), pp. 3168-3178. (doi: 10.1002/art.34581) (PMID:22729944)
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Abstract
Objective: Among many survival strategies, parasitic worms secrete molecules that modulate host immune responses. One such product, ES-62, is protective against collagen-induced arthritis (CIA), a model of rheumatoid arthritis (RA). Since interleukin-17 (IL-17) has been reported to play a pathogenic role in the development of RA, this study was undertaken to investigate whether targeting of IL-17 may explain the protection against CIA afforded by ES-62. <p/>Methods: 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 cell populations, and in situ analysis of joint inflammation in mice with CIA. <p/>Results: ES-62 was found to down-regulate IL-17 responses in mice with CIA. First, it acted to inhibit priming and polarization of IL-17 responses by targeting a complex IL-17–producing network, involving signaling between dendritic cells and γ/δ or CD4+ T cells. In addition, ES-62 directly targeted Th17 cells by down-regulating myeloid differentiation factor 88 expression to suppress responses mediated by IL-1 and Toll-like receptor ligands. Moreover, ES-62 modulated the migration of γ/δ T cells and this was reflected by direct suppression of CD44 up-regulation and, as evidenced by in situ analysis, dramatically reduced levels of IL-17–producing cells, including lymphocytes, infiltrating the joint. Finally, there was strong suppression of IL-17 production by cells resident in the joint, such as osteoclasts within the bone areas. <p/>Conclusion: Our findings indicate that ES-62 treatment of mice with CIA leads to unique multisite manipulation of the initiation and effector phases of the IL-17 inflammatory network. ES-62 could be exploited in the development of novel therapeutics for RA.
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Harnett, Professor Margaret and Al-Riyami, Dr Lamyaa and Rzepecka, Dr Justyna and Gracie, Professor Alastair and McGrath, Miss Mairi and Pineda, Dr Miguel |
Authors: | Pineda, M.A., McGrath, M.A., Smith, P.C., Al-Riyami, L., Rzepecka, J., Gracie, J.A., Harnett, W., and Harnett, M.M. |
College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
Journal Name: | Arthritis and Rheumatism |
Publisher: | John Wiley & Sons, Inc. |
ISSN: | 0004-3591 |
ISSN (Online): | 2326-5205 |
Published Online: | 27 September 2012 |
Copyright Holders: | Copyright © 2012 American College of Rheumatology |
First Published: | First published in Arthritis and Rheumatism 64(10):3168-3178 |
Publisher Policy: | Reproduced in accordance with the copyright policy of the publisher |
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