Antibody-mediated inhibition of TNFR1 attenuates disease in a mouse model of multiple sclerosis

Sarah K Williams; Olaf Maier; Roman Fischer; Richard Fairless; Sonja Hochmeister; Aleksandar Stojic; Lara Pick; Doreen Haar; Sylvia Musiol; Maria K Storch; Klaus Pfizenmaier; Ricarda Diem

doi:10.1371/journal.pone.0090117

Antibody-mediated inhibition of TNFR1 attenuates disease in a mouse model of multiple sclerosis

PLoS One. 2014 Feb 28;9(2):e90117. doi: 10.1371/journal.pone.0090117. eCollection 2014.

Authors

Affiliations

¹ Department of Neuro-oncology, University Clinic Heidelberg, Heidelberg, Germany.
² Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.
³ Department of Neurology, Medical University of Graz, Graz, Austria.
⁴ Department of Neurology, University of the Saarland, Homburg/Saar, Germany.

Abstract

Tumour necrosis factor (TNF) is a proinflammatory cytokine that is known to regulate inflammation in a number of autoimmune diseases, including multiple sclerosis (MS). Although targeting of TNF in models of MS has been successful, the pathological role of TNF in MS remains unclear due to clinical trials where the non-selective inhibition of TNF resulted in exacerbated disease. Subsequent experiments have indicated that this may have resulted from the divergent effects of the two TNF receptors, TNFR1 and TNFR2. Here we show that the selective targeting of TNFR1 with an antagonistic antibody ameliorates symptoms of the most common animal model of MS, experimental autoimmune encephalomyelitis (EAE), when given following both a prophylactic and therapeutic treatment regime. Our results demonstrate that antagonistic TNFR1-specific antibodies may represent a therapeutic approach for the treatment of MS in the future.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies / pharmacology*
Disease Models, Animal
Encephalomyelitis, Autoimmune, Experimental / genetics
Encephalomyelitis, Autoimmune, Experimental / immunology
Encephalomyelitis, Autoimmune, Experimental / pathology
Encephalomyelitis, Autoimmune, Experimental / therapy*
Female
Gene Expression
Immunotherapy*
Mice
Mice, Inbred C57BL
Mice, Knockout
Molecular Targeted Therapy
Multiple Sclerosis / genetics
Multiple Sclerosis / immunology
Multiple Sclerosis / pathology
Multiple Sclerosis / therapy
Receptors, Tumor Necrosis Factor, Type I / antagonists & inhibitors*
Receptors, Tumor Necrosis Factor, Type I / deficiency
Receptors, Tumor Necrosis Factor, Type I / genetics
Receptors, Tumor Necrosis Factor, Type II / antagonists & inhibitors
Receptors, Tumor Necrosis Factor, Type II / deficiency
Receptors, Tumor Necrosis Factor, Type II / genetics

Substances

Antibodies
Receptors, Tumor Necrosis Factor, Type I
Receptors, Tumor Necrosis Factor, Type II
Tnfrsf1a protein, mouse

Grants and funding

This work was supported by grants from the EC FP6, Project NeuroproMiSe (LSHM-CT-2005-018637) and the Hertie Foundation (1.01.1/12/008). The funders had no role in study design, data collection and analysis, decision to publish, or preparation on the manuscript.