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...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2018-09-01
|
| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-018-31957-7 |
| _version_ | 1818345614239334400 |
|---|---|
| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-13T17:05:10Z |
| format | Article |
| id | doaj.art-1d5fda7e325a49d7ac87de90f8d6525b |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-13T17:05:10Z |
| publishDate | 2018-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-1d5fda7e325a49d7ac87de90f8d6525b2022-12-21T23:37:42ZengNature PortfolioScientific Reports2045-23222018-09-018111410.1038/s41598-018-31957-7Anti-TNFR1 targeting in humanized mice ameliorates disease in a model of multiple sclerosisSarah K. Williams0Richard Fairless1Olaf Maier2Patricia C. Liermann3Kira Pichi4Roman Fischer5Ulrich L. M. Eisel6Roland Kontermann7Andreas Herrmann8Babette Weksler9Nacho Romero10Pierre-Olivier Couraud11Klaus Pfizenmaier12Ricarda Diem13Department of Neurology, University Clinic HeidelbergDepartment of Neurology, University Clinic HeidelbergInstitute of Cell Biology and Immunology, University of StuttgartDepartment of Neurology, University Clinic HeidelbergDepartment of Neurology, University Clinic HeidelbergInstitute of Cell Biology and Immunology, University of StuttgartDepartment of Molecular Neurobiology, Groningen Institute of Evolutionary Life Science, Faculty of Science and Engineering, University of GroningenInstitute of Cell Biology and Immunology, University of StuttgartBaliopharm AGWeill Medical College of Cornell UniversityDepartment of Life, Health and Chemical Sciences, The Open UniversityINSERM, U1016, Institut CochinInstitute of Cell Biology and Immunology, University of StuttgartDepartment of Neurology, University Clinic HeidelbergAbstract 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.https://doi.org/10.1038/s41598-018-31957-7TNF Receptor (TNFR1)Immune Cell CompositionCentral Nervous System Immune CellsExperimental Autoimmune EncephalomyelitisAnti-drug Antibodies (ADAs) |
| spellingShingle | 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 Scientific Reports TNF Receptor (TNFR1) Immune Cell Composition Central Nervous System Immune Cells Experimental Autoimmune Encephalomyelitis Anti-drug Antibodies (ADAs) |
| title | 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_short | 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 |
| topic | TNF Receptor (TNFR1) Immune Cell Composition Central Nervous System Immune Cells Experimental Autoimmune Encephalomyelitis Anti-drug Antibodies (ADAs) |
| url | https://doi.org/10.1038/s41598-018-31957-7 |
| 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 |