Abstract Details

Title A Mouse Model of Meningeal Inflammation and Subpial Demyelination Identifies an IL-17-mediated Mechanism of Cortical Injury that is Inhibited by Siponimod Therapy

Topic Multiple Sclerosis

Presentation(s) S12 - Progressive Multiple Sclerosis (1:11 PM-1:22 PM)

Poster/Presentation
Number 002

Objective To identify mechanisms of subpial cortical injury in a mouse model of MS-like pathology with meningeal inflammation and supbial demyelination.

Background Subpial demyelination is a specific hallmark of multiple sclerosis (MS) and a correlate of disease progression and cognitive decline. While subpial pathology may be driven by an immune response constrained to the inflamed meninges, the mechanism(s) that mediate pathogenesis in this compartment remain unclear.

Design/Methods

Using immunohistochemistry, we characterized a newly developed adoptive transfer (A/T) experimental autoimmune encephalomyelitis (EAE) mouse model of MS-like pathology. To test the role of lymphocyte trafficking from the periphery into the brain, A/T EAE mice were treated with siponimod, a selective sphingosine 1-phosphate (S1P) receptor_1,5 modulator that was recently shown to reduce disability progression in patients with MS. Congenic markers were used to differentiate between endogenous (CD45.1⁺) or transferred (CD45.2⁺) T cells within the CNS.

Results Proteolipid protein-specific Th17 cells, adoptively transferred into SJL/J recipient mice, induced EAE accompanied by extensive stromal cell remodelling and accumulation of B220⁺B cells and CD3⁺T cells in the brain meninges. These meningeal immune cells, overlaid areas of subpial cortical demyelination associated with microglial/macrophage activation, astrogliosis and disruption of the glial limitans. Siponimod treatment significantly ameliorated clinical EAE concomitant with reduced meningeal inflammation and subpial pathology. In addition, we found that siponimod treatment decreases the number and frequency of transferred but not endogenous T cells that migrate to CNS during EAE, and this effect was specific for IL-17-producing CD45.2⁺T cells (including IL-17⁺IFNγ⁺, IL-17⁺GM-CSF⁺and IL-17⁺IFNg⁺GM-CSF⁺).

Conclusions We conclude that the recently reported protective effects of siponimod therapy in MS may be mediated by a reduced accumulation of immune cells in the meninges, suppression of IL-17-producing lymphocytes in the CNS, and a concomitant reduction in demyelination and inflammation in the supbial cortex.

Authors/Disclosures
Valeria Ramaglia PRESENTER	No disclosure on file
Dennis Lee	No disclosure on file
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Barbara Nuesslein-Hildesheim, PhD (Novartis Pharma AG)	Dr. Nuesslein-Hildesheim has received personal compensation for serving as an employee of Novartis Pharma AG. Dr. Nuesslein-Hildesheim has stock in Novartis Pharma AG.
	No disclosure on file
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