FTY720 ameliorates MOG-induced experimental autoimmune encephalomyelitis by suppressing both cellular and humoral immune responses.
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 IgG(2a) 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-gamma, 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.
Papadopoulos
Dimitrios
D
Department of Cellular and Molecular Neuroscience, Division of Neuroscience, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom.
Rundle
Jon
J
Patel
Ryan
R
Marshall
Ian
I
Stretton
Jennifer
J
Eaton
Rachel
R
Richardson
Jill C
JC
Gonzalez
Maria I
MI
Philpott
Karen L
KL
Reynolds
Richard
R
D000818:Animals; D001323:Autoantibodies / Q000378:metabolism; D001369:Axons / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D000068876:Fingolimod Hydrochloride; D015870:Gene Expression / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects; D009103:Multiple Sclerosis; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D011409:Propylene Glycols / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins; D012720:Severity of Illness Index; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D013997:Time Factors
D001323:Autoantibodies; D007166:Immunosuppressive Agents; C571328:Mog protein, rat; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D011409:Propylene Glycols; D011994:Recombinant Proteins; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine