TNFR1 inhibition with a Nanobody protects against EAE development in mice

Abstract TNF has as detrimental role in multiple sclerosis (MS), however, anti-TNF medication is not working. Selective TNF/TNFR1 inhibition whilst sparing TNFR2 signaling reduces the pro-inflammatory effects of TNF but preserves the important neuroprotective signals via TNFR2. We previously reporte...

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Autores principales:	Sophie Steeland, Sara Van Ryckeghem, Griet Van Imschoot, Riet De Rycke, Wendy Toussaint, Leen Vanhoutte, Christian Vanhove, Filip De Vos, Roosmarijn E. Vandenbroucke, Claude Libert
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/134cd08380a44884a58fb5e4a1d4b55b
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spelling	oai:doaj.org-article:134cd08380a44884a58fb5e4a1d4b55b2021-12-02T15:05:20ZTNFR1 inhibition with a Nanobody protects against EAE development in mice10.1038/s41598-017-13984-y2045-2322https://doaj.org/article/134cd08380a44884a58fb5e4a1d4b55b2017-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-13984-yhttps://doaj.org/toc/2045-2322Abstract TNF has as detrimental role in multiple sclerosis (MS), however, anti-TNF medication is not working. Selective TNF/TNFR1 inhibition whilst sparing TNFR2 signaling reduces the pro-inflammatory effects of TNF but preserves the important neuroprotective signals via TNFR2. We previously reported the generation of a Nanobody-based selective inhibitor of human TNFR1, TROS that will be tested in experimental autoimmune encephalomyelitis (EAE). We specifically antagonized TNF/TNFR1 signaling using TROS in a murine model of MS, namely MOG35-55-induced EAE. Because TROS does not cross-react with mouse TNFR1, we generated mice expressing human TNFR1 in a mouse TNFR1-knockout background (hTNFR1 Tg), and we determined biodistribution of 99mTc-TROS and effectiveness of TROS in EAE in those mice. Biodistribution analysis demonstrated that intraperitoneally injected TROS is retained more in organs of hTNFR1 Tg mice compared to wild type mice. TROS was also detected in the cerebrospinal fluid (CSF) of hTNFR1 Tg mice. Prophylactic TROS administration significantly delayed disease onset and ameliorated its symptoms. Moreover, treatment initiated early after disease onset prevented further disease development. TROS reduced spinal cord inflammation and neuroinflammation, and preserved myelin and neurons. Collectively, our data illustrate that TNFR1 is a promising therapeutic target in MS.Sophie SteelandSara Van RyckeghemGriet Van ImschootRiet De RyckeWendy ToussaintLeen VanhoutteChristian VanhoveFilip De VosRoosmarijn E. VandenbrouckeClaude LibertNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-17 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sophie Steeland Sara Van Ryckeghem Griet Van Imschoot Riet De Rycke Wendy Toussaint Leen Vanhoutte Christian Vanhove Filip De Vos Roosmarijn E. Vandenbroucke Claude Libert TNFR1 inhibition with a Nanobody protects against EAE development in mice
description	Abstract TNF has as detrimental role in multiple sclerosis (MS), however, anti-TNF medication is not working. Selective TNF/TNFR1 inhibition whilst sparing TNFR2 signaling reduces the pro-inflammatory effects of TNF but preserves the important neuroprotective signals via TNFR2. We previously reported the generation of a Nanobody-based selective inhibitor of human TNFR1, TROS that will be tested in experimental autoimmune encephalomyelitis (EAE). We specifically antagonized TNF/TNFR1 signaling using TROS in a murine model of MS, namely MOG35-55-induced EAE. Because TROS does not cross-react with mouse TNFR1, we generated mice expressing human TNFR1 in a mouse TNFR1-knockout background (hTNFR1 Tg), and we determined biodistribution of 99mTc-TROS and effectiveness of TROS in EAE in those mice. Biodistribution analysis demonstrated that intraperitoneally injected TROS is retained more in organs of hTNFR1 Tg mice compared to wild type mice. TROS was also detected in the cerebrospinal fluid (CSF) of hTNFR1 Tg mice. Prophylactic TROS administration significantly delayed disease onset and ameliorated its symptoms. Moreover, treatment initiated early after disease onset prevented further disease development. TROS reduced spinal cord inflammation and neuroinflammation, and preserved myelin and neurons. Collectively, our data illustrate that TNFR1 is a promising therapeutic target in MS.
format	article
author	Sophie Steeland Sara Van Ryckeghem Griet Van Imschoot Riet De Rycke Wendy Toussaint Leen Vanhoutte Christian Vanhove Filip De Vos Roosmarijn E. Vandenbroucke Claude Libert
author_facet	Sophie Steeland Sara Van Ryckeghem Griet Van Imschoot Riet De Rycke Wendy Toussaint Leen Vanhoutte Christian Vanhove Filip De Vos Roosmarijn E. Vandenbroucke Claude Libert
author_sort	Sophie Steeland
title	TNFR1 inhibition with a Nanobody protects against EAE development in mice
title_short	TNFR1 inhibition with a Nanobody protects against EAE development in mice
title_full	TNFR1 inhibition with a Nanobody protects against EAE development in mice
title_fullStr	TNFR1 inhibition with a Nanobody protects against EAE development in mice
title_full_unstemmed	TNFR1 inhibition with a Nanobody protects against EAE development in mice
title_sort	tnfr1 inhibition with a nanobody protects against eae development in mice
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/134cd08380a44884a58fb5e4a1d4b55b
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TNFR1 inhibition with a Nanobody protects against EAE development in mice

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