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Keywords:

  • FTY720;
  • immunosuppression;
  • EAE;
  • MOG;
  • multiple sclerosis;
  • axon loss;
  • neurodegeneration;
  • demyelination;
  • sphingosine 1-phosphate receptors

Abstract

FTY720, an oral sphingosine 1-phosphate (S1P) receptor modulator, has shown efficacy in phase II trials in patients with relapsing-remitting multiple sclerosis (MS). Although this molecule is thought to immunosuppress by inhibiting lymphocyte egress from the lymph nodes, the full spectrum of FTY720's actions has not yet been uncovered. In this study, we investigated the effects of FTY720 treatment on disease severity and histopathology of MOG-induced experimental autoimmune encephalomyelitis (EAE) in the dark agouti (DA) rat, a model that closely mimics several features of MS. The effects of FTY720 on T-cell subsets, anti-MOG antibody production, and mRNA expression of a number of cytokines and other genes were also examined. Commencement of treatment before disease onset prevented the appearance of clinical disease. Therapeutic treatment after established disease reduced clinical scores and substantially attenuated inflammation, demyelination, and axon loss. EAE suppression was associated with a reduction in all measured T-cell subsets in blood and spleen and a significant decrease in serum IgG2a levels. However, in the lymph nodes, all T-cell subsets except for naïve T cells and recent thymic emigrants remained unaffected. In addition, FTY720 treatment led to a significant inhibition in interferon-γ, inducible nitric oxide synthase, and glial cell line-derived neurotrophic factor mRNA expression in the MOG-EAE spinal cord. In conclusion, our findings indicate that FTY720-mediated S1P receptor modulation ameliorates chronic relapsing MOG-EAE by suppressing both cellular and humoral immune responses. © 2009 Wiley-Liss, Inc.