Anti-TNFR1 targeting in humanized mice ameliorates disease in a model of multiple sclerosis

Abstract Tumour necrosis factor (TNF) signalling is mediated via two receptors, TNF-receptor 1 (TNFR1) and TNF-receptor 2 (TNFR2), which work antithetically to balance CNS immune responses involved in autoimmune diseases such as multiple sclerosis. To determine the therapeutic potential of selective...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Sarah K. Williams, Richard Fairless, Olaf Maier, Patricia C. Liermann, Kira Pichi, Roman Fischer, Ulrich L. M. Eisel, Roland Kontermann, Andreas Herrmann, Babette Weksler, Nacho Romero, Pierre-Olivier Couraud, Klaus Pfizenmaier, Ricarda Diem
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	TNF Receptor (TNFR1) Immune Cell Composition Central Nervous System Immune Cells Experimental Autoimmune Encephalomyelitis Anti-drug Antibodies (ADAs) Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1d5fda7e325a49d7ac87de90f8d6525b
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:1d5fda7e325a49d7ac87de90f8d6525b
record_format	dspace
spelling	oai:doaj.org-article:1d5fda7e325a49d7ac87de90f8d6525b2021-12-02T15:08:57ZAnti-TNFR1 targeting in humanized mice ameliorates disease in a model of multiple sclerosis10.1038/s41598-018-31957-72045-2322https://doaj.org/article/1d5fda7e325a49d7ac87de90f8d6525b2018-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-31957-7https://doaj.org/toc/2045-2322Abstract Tumour necrosis factor (TNF) signalling is mediated via two receptors, TNF-receptor 1 (TNFR1) and TNF-receptor 2 (TNFR2), which work antithetically to balance CNS immune responses involved in autoimmune diseases such as multiple sclerosis. To determine the therapeutic potential of selectively inhibiting TNFR1 in mice with experimental autoimmune encephalomyelitis, we used chimeric human/mouse TNFR1 knock-in mice allowing the evaluation of antagonistic anti-human TNFR1 antibody efficacy. Treatment of mice after onset of disease with ATROSAB resulted in a robust amelioration of disease severity, correlating with reduced central nervous system immune cell infiltration. Long-term efficacy of treatment was achieved by treatment with the parental mouse anti-human TNFR1 antibody, H398, and extended by subsequent re-treatment of mice following relapse. Our data support the hypothesis that anti-TNFR1 therapy restricts immune cell infiltration across the blood-brain barrier through the down-regulation of TNF-induced adhesion molecules, rather than altering immune cell composition or activity. Collectively, we demonstrate the potential for anti-human TNFR1 therapies to effectively modulate immune responses in autoimmune disease.Sarah K. WilliamsRichard FairlessOlaf MaierPatricia C. LiermannKira PichiRoman FischerUlrich L. M. EiselRoland KontermannAndreas HerrmannBabette WekslerNacho RomeroPierre-Olivier CouraudKlaus PfizenmaierRicarda DiemNature PortfolioarticleTNF Receptor (TNFR1)Immune Cell CompositionCentral Nervous System Immune CellsExperimental Autoimmune EncephalomyelitisAnti-drug Antibodies (ADAs)MedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-14 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	TNF Receptor (TNFR1) Immune Cell Composition Central Nervous System Immune Cells Experimental Autoimmune Encephalomyelitis Anti-drug Antibodies (ADAs) Medicine R Science Q
spellingShingle	TNF Receptor (TNFR1) Immune Cell Composition Central Nervous System Immune Cells Experimental Autoimmune Encephalomyelitis Anti-drug Antibodies (ADAs) Medicine R Science Q Sarah K. Williams Richard Fairless Olaf Maier Patricia C. Liermann Kira Pichi Roman Fischer Ulrich L. M. Eisel Roland Kontermann Andreas Herrmann Babette Weksler Nacho Romero Pierre-Olivier Couraud Klaus Pfizenmaier Ricarda Diem Anti-TNFR1 targeting in humanized mice ameliorates disease in a model of multiple sclerosis
description	Abstract Tumour necrosis factor (TNF) signalling is mediated via two receptors, TNF-receptor 1 (TNFR1) and TNF-receptor 2 (TNFR2), which work antithetically to balance CNS immune responses involved in autoimmune diseases such as multiple sclerosis. To determine the therapeutic potential of selectively inhibiting TNFR1 in mice with experimental autoimmune encephalomyelitis, we used chimeric human/mouse TNFR1 knock-in mice allowing the evaluation of antagonistic anti-human TNFR1 antibody efficacy. Treatment of mice after onset of disease with ATROSAB resulted in a robust amelioration of disease severity, correlating with reduced central nervous system immune cell infiltration. Long-term efficacy of treatment was achieved by treatment with the parental mouse anti-human TNFR1 antibody, H398, and extended by subsequent re-treatment of mice following relapse. Our data support the hypothesis that anti-TNFR1 therapy restricts immune cell infiltration across the blood-brain barrier through the down-regulation of TNF-induced adhesion molecules, rather than altering immune cell composition or activity. Collectively, we demonstrate the potential for anti-human TNFR1 therapies to effectively modulate immune responses in autoimmune disease.
format	article
author	Sarah K. Williams Richard Fairless Olaf Maier Patricia C. Liermann Kira Pichi Roman Fischer Ulrich L. M. Eisel Roland Kontermann Andreas Herrmann Babette Weksler Nacho Romero Pierre-Olivier Couraud Klaus Pfizenmaier Ricarda Diem
author_facet	Sarah K. Williams Richard Fairless Olaf Maier Patricia C. Liermann Kira Pichi Roman Fischer Ulrich L. M. Eisel Roland Kontermann Andreas Herrmann Babette Weksler Nacho Romero Pierre-Olivier Couraud Klaus Pfizenmaier Ricarda Diem
author_sort	Sarah K. Williams
title	Anti-TNFR1 targeting in humanized mice ameliorates disease in a model of multiple sclerosis
title_short	Anti-TNFR1 targeting in humanized mice ameliorates disease in a model of multiple sclerosis
title_full	Anti-TNFR1 targeting in humanized mice ameliorates disease in a model of multiple sclerosis
title_fullStr	Anti-TNFR1 targeting in humanized mice ameliorates disease in a model of multiple sclerosis
title_full_unstemmed	Anti-TNFR1 targeting in humanized mice ameliorates disease in a model of multiple sclerosis
title_sort	anti-tnfr1 targeting in humanized mice ameliorates disease in a model of multiple sclerosis
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/1d5fda7e325a49d7ac87de90f8d6525b
work_keys_str_mv	AT sarahkwilliams antitnfr1targetinginhumanizedmiceamelioratesdiseaseinamodelofmultiplesclerosis AT richardfairless antitnfr1targetinginhumanizedmiceamelioratesdiseaseinamodelofmultiplesclerosis AT olafmaier antitnfr1targetinginhumanizedmiceamelioratesdiseaseinamodelofmultiplesclerosis AT patriciacliermann antitnfr1targetinginhumanizedmiceamelioratesdiseaseinamodelofmultiplesclerosis AT kirapichi antitnfr1targetinginhumanizedmiceamelioratesdiseaseinamodelofmultiplesclerosis AT romanfischer antitnfr1targetinginhumanizedmiceamelioratesdiseaseinamodelofmultiplesclerosis AT ulrichlmeisel antitnfr1targetinginhumanizedmiceamelioratesdiseaseinamodelofmultiplesclerosis AT rolandkontermann antitnfr1targetinginhumanizedmiceamelioratesdiseaseinamodelofmultiplesclerosis AT andreasherrmann antitnfr1targetinginhumanizedmiceamelioratesdiseaseinamodelofmultiplesclerosis AT babetteweksler antitnfr1targetinginhumanizedmiceamelioratesdiseaseinamodelofmultiplesclerosis AT nachoromero antitnfr1targetinginhumanizedmiceamelioratesdiseaseinamodelofmultiplesclerosis AT pierreoliviercouraud antitnfr1targetinginhumanizedmiceamelioratesdiseaseinamodelofmultiplesclerosis AT klauspfizenmaier antitnfr1targetinginhumanizedmiceamelioratesdiseaseinamodelofmultiplesclerosis AT ricardadiem antitnfr1targetinginhumanizedmiceamelioratesdiseaseinamodelofmultiplesclerosis
_version_	1718387924260618240

Anti-TNFR1 targeting in humanized mice ameliorates disease in a model of multiple sclerosis

Ejemplares similares