1. Brinkmann, V. Et Al. the Immune Modulator FTY720 Targets Sphingosine 1-Phosphate Receptors

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

 Wistar rats  Active  Bovine spinal  Preventive  Complete disease  Not applicable  Not applicable 1 cord approach prevention

 0.3 mg/kg orally

 Lewis rats  Active  MBP  Preventive  Near complete  Decreased infiltration of T  Decreased expression of IL-2, 2

(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

 SJL mice  Active  PLP139–151  Therapeutic  Reduction of disease  Not applicable  Reduced downregulation of 3 (female) approach score myelin compounds

treatment at  Dose dependent  Reduced upregulation of and after correlation of disease inflammatory cytokines on disease severity to treatment RNA level

onset with initiation and  Lymphopenia 0.03–1 cessation mg/kg i.p.

 Passive  PLP139–151  Preventive approach

 SJL mice  Active  PLP  Preventive  Complete prevention  Not applicable  Lymphocyte sequestration in 4 approach of disease secondary lymphoid tissue

 0.03 and  Efficacy superior to 0.1 mg/kg i.p. rmIFN-β orally

 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

 SJL mice  Active  MOG35–55 therapeutic prevention at highest models lymphocytes

 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

 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

 0.4 mg/kg  Decreased demyelination orally and axonal loss in rescue approach

 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

approach  Reversal of  Complete absence of  Increased expression of  0.3 mg/kg established active lesions myelin-related genes

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.

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