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

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

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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.
Original languageEnglish
Article number13628
Number of pages14
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - 11-Sep-2018

Keywords

  • TUMOR-NECROSIS-FACTOR
  • EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS
  • EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS
  • CENTRAL-NERVOUS-SYSTEM
  • BLOOD-BRAIN-BARRIER
  • FACTOR-RECEPTOR
  • FACTOR-ALPHA
  • FACTOR TNF
  • CELL-LINE
  • THERAPY

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