Siponimod Hinders the Formation of meningeal Ectopic Lymphoid Tissue in a Mouse Model of Multiple Sclerosis

Objective: To study the effect of siponimod on the formation of meningeal ectopic lymphoid tissue (mELT) in a model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). Background: MS is the most common inflammatory disease of the central nervous system (CNS). The presence of mELT in MS patients is associated with a more severe disease course and pronounced cortical pathology, particularly in progressive stages. However the role of mELT in the pathogenesis of MS, if any, remains obscure and it is unclear whether mELT represents a therapeutic target. Siponimod is a selective sphingosin-1-phosphate (S1P) receptor modulator approved for the treatment of relapsing-remitting and active secondary progressive MS. Design/Methods: Since mELT is currently not accessible for in vivo studies, we utilized a model of MS. 2D2xTH mice develop spontaneous EAE and mELT along the spinal cord. They were treated with oral siponimod (3 mg/kg body weight) or vehicle daily for 30 days, starting prior to the onset of EAE in an attempt to attenuate EAE and prevent the formation of mELT. In addition to the clinical disease score, we histologically assessed the size and composition of mELT. Results: 2D2xTH mice treated with siponimod in a preventative manner had a milder clinical disease course compared to controls (mean EAE score on day 22, 1.0 ±0.55 SEM, siponimod, versus 2.8 ±0.25 SEM, vehicle). Although siponimod did not entirely prevent the formation of spinal cord mELT, it significantly reduced its extent (mean area of mELT/section in μm2, 23,857 ±7,953 SEM, siponimod, versus 112,189 ±20,725 SEM, vehicle). Conclusions: Our data demonstrate that preventative siponimod treatment hinders the formation of mELT in EAE and is associated with a milder disease course. Ongoing experiments address how siponimod affects the cellular composition of remaining mELT. Our findings help to better understand the effects of siponimod on CNS inflammation. Disclosure: Dr. Brand has nothing to disclose. Dr. Pfaller has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Novartis (compensation for travel expenses). Dr. Diddens has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Novartis. Dr. Steiger has nothing to disclose. Dr. Lehmann-Horn has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Hoffmann-La Roche, Novartis, Merck Serono. Dr. Lehmann-Horn has received research support from Novartis.