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

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 inflamm...

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Autores principales:	Felicity E. Lumb, James Doonan, Kara S. Bell, Miguel A. Pineda, Marlene Corbet, Colin J. Suckling, Margaret M. Harnett, William Harnett
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/630b811b03324ca2ba57f8104374c764
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spelling	oai:doaj.org-article:630b811b03324ca2ba57f8104374c7642021-12-02T11:52:57ZDendritic cells provide a therapeutic target for synthetic small molecule analogues of the parasitic worm product, ES-6210.1038/s41598-017-01651-12045-2322https://doaj.org/article/630b811b03324ca2ba57f8104374c7642017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01651-1https://doaj.org/toc/2045-2322Abstract 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.Felicity E. LumbJames DoonanKara S. BellMiguel A. PinedaMarlene CorbetColin J. SucklingMargaret M. HarnettWilliam HarnettNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Felicity E. Lumb James Doonan Kara S. Bell Miguel A. Pineda Marlene Corbet Colin J. Suckling Margaret M. Harnett William Harnett Dendritic cells provide a therapeutic target for synthetic small molecule analogues of the parasitic worm product, ES-62
description	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.
format	article
author	Felicity E. Lumb James Doonan Kara S. Bell Miguel A. Pineda Marlene Corbet Colin J. Suckling Margaret M. Harnett William Harnett
author_facet	Felicity E. Lumb James Doonan Kara S. Bell Miguel A. Pineda Marlene Corbet Colin J. Suckling Margaret M. Harnett William Harnett
author_sort	Felicity E. Lumb
title	Dendritic cells provide a therapeutic target for synthetic small molecule analogues of the parasitic worm product, ES-62
title_short	Dendritic cells provide a therapeutic target for synthetic small molecule analogues of the parasitic worm product, ES-62
title_full	Dendritic cells provide a therapeutic target for synthetic small molecule analogues of the parasitic worm product, ES-62
title_fullStr	Dendritic cells provide a therapeutic target for synthetic small molecule analogues of the parasitic worm product, ES-62
title_full_unstemmed	Dendritic cells provide a therapeutic target for synthetic small molecule analogues of the parasitic worm product, ES-62
title_sort	dendritic cells provide a therapeutic target for synthetic small molecule analogues of the parasitic worm product, es-62
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/630b811b03324ca2ba57f8104374c764
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Dendritic cells provide a therapeutic target for synthetic small molecule analogues of the parasitic worm product, ES-62

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