FTY720 (fingolimod) treatment tips the balance towards less immunogenic antigen-presenting cells in patients with multiple sclerosis.
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.
Department of Neurology, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany luessi@uni-mainz.de.
Felix
F
Luessi
Department of Neurology, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany.
Stefan
S
Kraus
Department of Dermatology, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany.
Bettina
B
Trinschek
Department of Neurology, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany.
Steffen
S
Lerch
Department of Neurology, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany.
Robert
R
Ploen
Department of Neurology, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany.
Magdalena
M
Paterka
Department of Neurology, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany.
Torsten
T
Roberg
Department of Neurology, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany.
Laura
L
Poisa-Beiro
Department of Neurology, University of Münster, Germany.
Luisa
L
Klotz
Department of Neurology, University of Münster, Germany.
Heinz
H
Wiendl
Institute for Immunology, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany.
Tobias
T
Bopp
Department of Dermatology, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany.
Helmut
H
Jonuleit
Department of Neurology, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany.
Valérie
V
Jolivel
Department of Neurology, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany.
Frauke
F
Zipp
Department of Neurology, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany.
Esther
E
Witsch
D000328:Adult; D016207:Cytokines / Q000187:drug effects*; D003713:Dendritic Cells / Q000187:drug effects*; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects*; D009103:Multiple Sclerosis / Q000097:blood* / Q000188:drug therapy*; D055815:Young Adult
D016207:Cytokines; D007166:Immunosuppressive Agents; D000068876:Fingolimod Hydrochloride
Fingolimod; cytokine; dendritic cell; immunotherapy; monocyte; multiple sclerosis