title: Fingolimod additionally acts as immunomodulator focused on the innate immune system beyond its prominent effects on lymphocyte recirculation.
abstract: Growing evidence emphasizes the relevance of sphingolipids for metabolism and immunity of antigen-presenting cells (APC). APCs are key players in balancing tolerogenic and encephalitogenic responses in immunology. In contrast to the well-known prominent effects of sphingosine-1-phosphate (S1P) on lymphocyte trafficking, modulatory effects on APCs have not been fully characterized.
  
  
  
  Frequencies and activation profiles of dendritic cell (DC) subtypes, monocytes, and T cell subsets in 35 multiple sclerosis (MS) patients were evaluated prior and after undergoing fingolimod treatment for up to 24 months. Impact of fingolimod and S1P on maturation and activation profile, pro-inflammatory cytokine release, and phagocytotic capacity was assessed in vitro and ex vivo. Modulation of DC-dependent programming of naïve CD4+ T cells, as well as CD4+ and CD8+ T cell proliferation, was also investigated in vitro and ex vivo.
  
  
  
  Fingolimod increased peripheral slanDC count-CD1+ DC, and monocyte frequencies remained stable. While CD4+ T cell count decreased, ratio of Treg/Th17 significantly increased in fingolimod-treated patients over time. CD83, CD150, and HLADR were all inhibited, but CD86 was upregulated in DCs after incubation in the presence of fingolimod. Fingolimod but not S1P was associated with reduced release of pro-inflammatory cytokines from DCs and monocytes in vitro and ex vivo. Fingolimod also inhibited phagocytic capacity of slanDCs and monocytes. After fingolimod, slanDCs demonstrated reduced potential to induce interferon-gamma-expressing Th1 or IL-17-expressing Th17 cells and DC-dependent T cell proliferation in vitro and in fingolimod-treated patients.
  
  
  
  We present the first evidence that S1P-directed therapies can act additionally as immunomodulators that decrease the pro-inflammatory capabilities of APCs, which is a crucial element in DC-dependent T cell activation and programming.
authors.affiliation: Center of Clinical Neuroscience, Department of Neurology, Carl Gustav Carus University Hospital, University of Technology Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Thomas
authors.affiliation: Center of Clinical Neuroscience, Department of Neurology, Carl Gustav Carus University Hospital, University of Technology Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
authors.forename: Tony
authors.initials: T
authors.lastname: Sehr
authors.affiliation: Center of Clinical Neuroscience, Department of Neurology, Carl Gustav Carus University Hospital, University of Technology Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
authors.forename: Undine
authors.initials: U
authors.lastname: Proschmann
authors.affiliation: Center of Clinical Neuroscience, Department of Neurology, Carl Gustav Carus University Hospital, University of Technology Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
authors.forename: Francisco Alejandro
authors.initials: FA
authors.lastname: Rodriguez-Leal
authors.affiliation: Center of Clinical Neuroscience, Department of Neurology, Carl Gustav Carus University Hospital, University of Technology Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
authors.forename: Rocco
authors.initials: R
authors.lastname: Haase
authors.affiliation: Center of Clinical Neuroscience, Department of Neurology, Carl Gustav Carus University Hospital, University of Technology Dresden, Fetscherstr. 74, 01307, Dresden, Germany. Tjalf.Ziemssen@uniklinikum-dresden.de.
authors.forename: Tjalf
authors.identifier: 0000-0001-8799-8202
authors.initials: T
authors.lastname: Ziemssen
mesh_terms: D000328:Adult; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology*; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects* / Q000276:immunology; D007155:Immunologic Factors / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood / Q000276:immunology; D055815:Young Adult
chemical_list: D007155:Immunologic Factors; D000068876:Fingolimod Hydrochloride
keywords: Antigen-presenting cells; Dendritic cells; Innate immunity; Multiple sclerosis; Sphingosine-1-phosphate-directed therapies