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Siponimod therapy implicates Th17 cells in a preclinical model of subpial cortical injury.

  • Ward LA Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
  • Lee DS Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
  • Sharma A Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
  • Wang A Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
  • Naouar I Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
  • Ma XI Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
  • Pikor N Institute of Immunobiology, Kantonsspital St Gallen, St Gallen, Switzerland.
  • Nuesslein-Hildesheim B Novartis Institutes for BioMedical Research, Basel, Switzerland.
  • Ramaglia V Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
  • Gommerman JL Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
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  • 2019-12-11
Published in:
  • JCI insight. - 2020
Immunology
Mouse models
Multiple sclerosis
T cells
English Subpial demyelination is a specific hallmark of multiple sclerosis and a correlate of disease progression. Although the mechanism(s) that mediate pathogenesis in the subpial compartment remain unclear, it has been speculated that inflammation in the overlying meninges may be associated with subpial injury. Here we show that adoptive transfer of proteolipid protein-primed Th17 cells into SJL/J recipient mice induces subpial demyelination associated with microglial/macrophage activation, disruption of the glial limitans, and evidence of an oxidative stress response. This pathology was topologically associated with foci of immune cells in the meninges and occurred in the absence of measurable anti-myelin oligodendrocyte glycoprotein IgM or IgG antibodies. To test the role of brain-infiltrating leukocytes on subpial injury, we modulated sphingosine 1-phosphate (S1P) receptor1,5 activity with BAF312 (siponimod) treatment. Administration of BAF312, even after adoptively transferred T cells had entered the brain, significantly ameliorated clinical experimental autoimmune encephalomyelitis and diminished subpial pathology, concomitant with a selective reduction in the capacity of transferred T cells to make Th17 cytokines. We conclude that sustained subpial cortical injury is associated with the capacity for brain-resident T cells to produce Th17 cytokines, and this pathological process occurs in an S1P receptor1,5-dependent manner.
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  • English
Open access status
gold
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https://sonar.ch/global/documents/55823
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