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