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

• DOI: 10.1172/jci.insight.132522
• Publication Date: 2019-12-10T17:01:18Z
• Authors: Lesley A. Ward; Dennis S.W. Lee; Anshu Sharma; Angela Wang; Ikbel Naouar; Xianjie I. Ma; Natalia Pikor; Barbara Nuesslein...; Valeria Ramaglia; Jennifer L. Gomme...
• Keywords: Inflammation; Encephalomyelitis, Autoimmune, Experimental; Multiple Sclerosis; Macrophages; Brain; Adoptive Transfer; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Meninges; 0302 clinical medicine; Immunoglobulin M; Cytidine Deaminase; Immunoglobulin G; Benzyl Compounds; Disease Progression; Animals; Azetidines; Cytokines; Female; Myelin-Oligodendrocyte Glycoprotein; Microglia

Subpial demyelination is a specific hallmark of multiple sclerosis and correlate disease progression. Although the mechanism(s) that mediate pathogenesis in subpial compartment remain unclear, it has been speculated inflammation overlying meninges may be associated with injury. Here we show adoptive transfer proteolipid protein-primed Th17 cells into SJL/J recipient mice induces microglial/macrophage activation, disruption glial limitans, evidence an oxidative stress response. This pathology was topologically foci immune occurred absence measurable anti-myelin oligodendrocyte glycoprotein IgM or IgG antibodies. To test role brain-infiltrating leukocytes on injury, modulated sphingosine 1-phosphate (S1P) receptor1,5 activity BAF312 (siponimod) treatment. Administration BAF312, even after adoptively transferred T had entered brain, significantly ameliorated clinical experimental autoimmune encephalomyelitis diminished pathology, concomitant selective reduction capacity to make cytokines. We conclude sustained cortical injury for brain-resident produce cytokines, this pathological process occurs S1P receptor1,5-dependent manner.