Dendritic cells provide a therapeutic target for synthetic small molecule analogues of the parasitic worm product, ES-62

Lumb, F. E., Doonan, J., Bell, K. S., Pineda, M. A., Corbet, M., Suckling, C. J., Harnett, M. M. and Harnett, W. (2017) Dendritic cells provide a therapeutic target for synthetic small molecule analogues of the parasitic worm product, ES-62. Scientific Reports, 7(1), 1704. (doi:10.1038/s41598-017-01651-1) (PMID:28490801) (PMCID:PMC5431997)

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Abstract

ES-62, a glycoprotein secreted by the parasitic filarial nematode Acanthocheilonema viteae, subverts host immune responses towards anti-inflammatory phenotypes by virtue of covalently attached phosphorylcholine (PC). The PC dictates that ES-62 exhibits protection in murine models of inflammatory disease and hence a library of drug-like PC-based small molecule analogues (SMAs) was synthesised. Four sulfone-containing SMAs termed 11a, 11e, 11i and 12b were found to reduce mouse bone marrow-derived dendritic cell (DC) pathogen-associated molecular pattern (PAMP)-induced pro-inflammatory cytokine production, inhibit NF-κB p65 activation, and suppress LPS-induced up-regulation of CD40 and CD86. Active SMAs also resulted in a DC phenotype that exhibited reduced capacity to prime antigen (Ag)-specific IFN-γ production during co-culture with naïve transgenic TCR DO.11.10 T cells in vitro and reduced their ability, following adoptive transfer, to prime the expansion of Ag-specific T lymphocytes, specifically TH17 cells, in vivo. Consistent with this, mice receiving DCs treated with SMAs exhibited significantly reduced severity of collagen-induced arthritis and this was accompanied by a significant reduction in IL-17+ cells in the draining lymph nodes. Collectively, these studies indicate that drug-like compounds that target DCs can be designed from parasitic worm products and demonstrate the potential for ES-62 SMA-based DC therapy in inflammatory disease.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Harnett, Professor Margaret and Lumb, Miss Felicity and Harnett, Professor William and Pineda, Dr Miguel and Doonan, Dr James
Authors: Lumb, F. E., Doonan, J., Bell, K. S., Pineda, M. A., Corbet, M., Suckling, C. J., Harnett, M. M., and Harnett, W.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Scientific Reports
Publisher:Nature Publishing Group
ISSN:2045-2322
ISSN (Online):2045-2322
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Scientific Reports 7(1):1704
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
495342ES-62, TLR4, the Mast Cell and development of novel drugs for mast cell-mediated inflammationMargaret HarnettWellcome Trust (WELLCOTR)086852/Z/08/ZIII -IMMUNOLOGY
484131Exploiting the host-parasite relationship to develop novel safe anti-inflammatory therapiesMargaret HarnettArthritis Research UK (ARTRESUK)MP/18413III -IMMUNOLOGY