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

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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

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 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.

References

1. Brinkmann, V. et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J. Biol. Chem. 277, 21453–21457 (2002).

2. Fujino, M. et al. Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment. J. Pharmacol. Exp. Ther. 305,

70–77 (2003).

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3. Webb, M. et al. Sphingosine 1-phosphate receptor agonists attenuate relapsing-remitting experimental autoimmune encephalitis in SJL mice. J.

Neuroimmunol. 153, 108–121 (2004).

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).

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).

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).

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).

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