Publication in detail

Sci Rep. 2018 Sep 11;8(1):13628. doi: 10.1038/s41598-018-31957-7.

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

Williams, SK; Fairless, R; Maier, O; Liermann, PC; Pichi, K; Fischer, R; Eisel, ULM; Kontermann, R; Weksler, B; Romero, N; Couraud, PO; Pfizenmaier, K; Diem, R

Department of Neurology, University Clinic Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany. Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany. Department of Molecular Neurobiology, Groningen Institute of Evolutionary Life Science, Faculty of Science and Engineering, University of Groningen, P.O. Box 11103, NL-9700, CC, Groningen, The Netherlands. Baliopharm AG, Eulerstr. 55, CH-4051, Basel, Switzerland. Weill Medical College of Cornell University, New York, NY, USA. Department of Life, Health and Chemical Sciences, The Open University, Milton Keynes, MK7 6AA, UK. INSERM, U1016, Institut Cochin, Paris, France.

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.

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