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FTY720 (fingolimod) treatment tips the balance towards less immunogenic antigen-presenting cells in patients with multiple sclerosis

2015; SAGE Publishing; Volume: 21; Issue: 14 Linguagem: Inglês

10.1177/1352458515574895

1477-0970

Felix Luessi, Stefan H.P. Kraus, Bettina Trinschek, Steffen Lerch, Robert Ploen, Magdalena Paterka, Torsten Roberg, Laura Poisa-Beiro, Luisa Klotz, Heinz Wiendl, Tobias Bopp, Helmut Jonuleit, Valérie Jolivel, Frauke Zipp, Esther Witsch,

Inflammasome and immune disorders

Objective: We aimed to clarify whether fingolimod has direct effects on antigen-presenting cells in multiple sclerosis patients. Methods: Frequency and phenotype of directly ex vivo dendritic cells and monocytes were analyzed in 43 individuals, including fingolimod-treated and untreated multiple sclerosis patients as well as healthy subjects. These cells were further stimulated with lipopolysaccharide to determine functional effects of fingolimod treatment. Results: Absolute numbers of CD1c+ dendritic cells and monocytes were not significantly reduced in fingolimod-treated patients indicating that fingolimod did not block the migration of antigen-presenting cells to peripheral blood. CD86 was upregulated on CD1c+ dendritic cells and thus their activation was not impaired under fingolimod treatment. Quantitative analyses of gene transcription in cells and protein content in supernatants from ex vivo CD1c+ dendritic cells and monocytes, however, showed lower secretion of TNFα, IL1-β and IL-6 upon lipopolysaccharide-stimulation. These results could be matched with CD4+MOG-specific transgenic T cells exhibiting reduced levels of TNFα and IFN-γ but not IL-4 upon stimulation with murine dendritic cells loaded with MOG, when treated with fingolimod. Conclusions: Our data indicate that fingolimod – apart from trapping lymphocytes in lymph nodes – exerts its disease-modulating activity by rebalancing the immune tolerance networks by modulation of antigen-presenting cells.