<p>Supplementary Table 1│Preclinical studies investigating the impact of fingolimod in experimental autoimmune encephalomyelitis. Model Disease Encephalitogenic Treatment Clinical outcome Mechanistic findings: Mechanistic findings: Citation induction antigen scenario histopathology immunology</p><p> Wistar rats  Active  Bovine spinal  Preventive  Complete disease  Not applicable  Not applicable 1 cord approach prevention</p><p> 0.3 mg/kg orally</p><p> Lewis rats  Active  MBP  Preventive  Near complete  Decreased infiltration of T  Decreased expression of IL-2, 2</p><p>(male)  Passive  MBP approach disease prevention cells and decreased IL-6 and IFN-γ in spinal cord  1 mg/kg  Complete prevention apoptosis rate in spinal but not in spleen (mRNA) orally of disease related cord  Immune cells from mortality fingolimod-treated animals show reduced encephalitogenicity</p><p> SJL mice  Active  PLP139–151  Therapeutic  Reduction of disease  Not applicable  Reduced downregulation of 3 (female) approach score myelin compounds</p><p> treatment at  Dose dependent  Reduced upregulation of and after correlation of disease inflammatory cytokines on disease severity to treatment RNA level</p><p> onset with initiation and  Lymphopenia 0.03–1 cessation mg/kg i.p.</p><p> Passive  PLP139–151  Preventive approach </p><p> SJL mice  Active  PLP  Preventive  Complete prevention  Not applicable  Lymphocyte sequestration in 4 approach of disease secondary lymphoid tissue</p><p> 0.03 and  Efficacy superior to 0.1 mg/kg i.p. rmIFN-β orally</p><p> Lewis rats  Active  MBP from  Preventive  Dose dependent with  Decreased inflammation  Decreased number of 5 (male) guinea pig and complete disease and demyelination in all circulating T and B </p><p> SJL mice  Active  MOG35–55 therapeutic prevention at highest models lymphocytes</p><p>1</p><p> C57BL/6  Active  PLP139–151 approach dose in all 3 models  Marked reduction of CNS-  Decreased IFN-γ expression + mice  0.1–1  Efficacy superior to infiltrating CD4 and (mRNA) in spinal cord mg/kg rmIFN-β and equal CD8+ T cells orally to prednisolone</p><p> Dark  Active  MOG1–125  Preventive  Amelioration of VEP  Reduced demyelination  Not applicable 6 Agouti rats and and SEP impairment and axonal loss in therapeutic preventive approach</p><p> 0.4 mg/kg  Decreased demyelination orally and axonal loss in rescue approach</p><p> Dark  Active  Syngeneic CNS  Preventive,  Preventive and  Decreased number and  Decreased expression of a 7 Agouti rats antigen therapeutic therapeutic area of lesions in spinal large variety of immune- and rescue approaches effective cord related genes in CNS tissue</p><p> approach  Reversal of  Complete absence of  Increased expression of  0.3 mg/kg established active lesions myelin-related genes</p><p> orally neurologic deficits  Restored expression of for late stage pathologically regulated S1P treatment receptors in brain Abbreviations: IFN, interferon; IL, interleukin; i.p, intraperitoneal; MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein; PLP, proteolipid protein; SEP, somatosensory evoked potentials; S1P, sphingosine-1-phosphate; VEP, visually evoked potentials. </p><p>References</p><p>1. Brinkmann, V. et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J. Biol. Chem. 277, 21453–21457 (2002).</p><p>2. Fujino, M. et al. Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment. J. Pharmacol. Exp. Ther. 305,</p><p>70–77 (2003).</p><p>2</p><p>3. Webb, M. et al. Sphingosine 1-phosphate receptor agonists attenuate relapsing-remitting experimental autoimmune encephalitis in SJL mice. J.</p><p>Neuroimmunol. 153, 108–121 (2004).</p><p>4. Chiba, K. et al. Immunosuppressive activity of FTY720, sphingosine 1-phosphate receptor agonist: I. Prevention of allograft rejection in rats and dogs by FTY720 and FTY720-phosphate. Transplant. Proc. 37, 102–106 (2005).</p><p>5. Kataoka, H. et al. FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration. Cell Mol. Immunol. 2, 439–448 (2005).</p><p>6. Balatoni, B. et al. FTY720 sustains and restores neuronal function in the DA rat model of MOG-induced experimental autoimmune encepha- lomyelitis. Brain Res. Bull. 74, 307–316 (2007).</p><p>7. Foster, C. A. et al. FTY720 rescue therapy in the dark agouti rat model of experimental autoimmune encephalomyelitis: expression of central nervous system genes and reversal of blood-brain-barrier damage. Brain Pathol. 19, 254–266 (2009).</p><p>3</p>