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

Abstract

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.

Keywords

Fingolimod multiple sclerosis dendritic cell monocyte cytokine immunotherapy

Get full access to this article

View all access options for this article.

References

Cohen

Barkhof

Comi

. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010; 362: 402–415.

Mandala

Hajdu

Bergstrom

. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 2002; 296: 346–349.

Matloubian

Cinamon

. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 2004; 427: 355–360.

Idzko

Panther

Corinti

. Sphingosine 1-phosphate induces chemotaxis of immature and modulates cytokine-release in mature human dendritic cells for emergence of Th2 immune responses. FASEB J 2002; 16: 625–627.

Okamoto

Takuwa

Gonda

. EDG1 is a functional sphingosine-1-phosphate receptor that is linked via a Gi/o to multiple signaling pathways, including phospholipase C activation, Ca2+ mobilization, Ras-mitogen-activated protein kinase activation, and adenylate cyclase inhibition. J Biol Chem 1998; 273: 27104–27110.

Maeda

Matsuyuki

Shimano

. Migration of CD4 T cells and dendritic cells toward sphingosine 1-phosphate (S1P) is mediated by different receptor subtypes: S1P regulates the functions of murine mature dendritic cells via S1P receptor type 3. J Immunol 2007; 178: 3437–3446.

Muller

Hofer

Kaneider

. The immunomodulator FTY720 interferes with effector functions of human monocyte-derived dendritic cells. Eur J Immunol 2005; 35: 533–545.

Lidington

McCormack

Yacoub

. The effects of monocytes on the transendothelial migration of T lymphocytes. Immunology 1998; 94: 221–227.

Kowarik

Pellkofer

Cepok

. Differential effects of fingolimod (FTY720) on immune cells in the CSF and blood of patients with MS. Neurology 2011; 76: 1214–1221.

10.

Lewis

Haxhinasto

Anderson

. Circulating monocytes are reduced by sphingosine-1-phosphate receptor modulators independently of S1P3. J Immunol 2013; 190: 3533–3540.

11.

Jolivel

Luessi

Masri

. Modulation of dendritic cell properties by laquinimod as a mechanism for modulating multiple sclerosis. Brain 2013; 136: 1048–1066.

12.

Kraus

Luessi

Trinschek

. Cladribine exerts an immunomodulatory effect on human and murine dendritic cells. Int Immunopharmacol 2014; 18: 347–357.

13.

Hiscott

Marois

Garoufalis

. Characterization of a functional NF-kappa B site in the human interleukin 1 beta promoter: evidence for a positive autoregulatory loop. Mol Cell Biol 1993; 13: 6231–6240.

14.

Noor

Wilson

. Role of C-C chemokine receptor type 7 and its ligands during neuroinflammation. J Neuroinflammation 2012; 9: 77.

15.

Kramer

Binder

Loof

. The lymphocyte migration inhibitor FTY720 attenuates experimental hypertensive nephropathy. Am J Physiol Renal Physiol 2009; 297: F218–227.

16.

Weber

Prod’homme

Youssef

. Type II monocytes modulate T cell-mediated central nervous system autoimmune disease. Nat Med 2007; 13: 935–943.

17.

Lutz

Schuler

. Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity? Trends Immunol 2002; 23: 445–449.

18.

Sicotte

Liva

Klutch

. Treatment of multiple sclerosis with the pregnancy hormone estriol. Ann Neurol 2002; 52: 421–428.

19.

Papenfuss

Powell

McClain

. Estriol generates tolerogenic dendritic cells in vivo that protect against autoimmunity. J Immunol 2011; 186: 3346–3355.

20.

Galicia-Rosas

Pikor

Schwartz

. A sphingosine-1-phosphate receptor 1-directed agonist reduces central nervous system inflammation in a plasmacytoid dendritic cell-dependent manner. J Immunol 2012; 189: 3700–3706.

21.

Zeng

Wang

Zhu

. Topographical and biological evidence revealed FTY720-mediated anergy-polarization of mouse bone marrow-derived dendritic cells in vitro. PLoS One 2012; 7: e34830.

22.

Leech

Barr

Turner

. Cutting edge: IL-6-dependent autoimmune disease: dendritic cells as a sufficient, but transient, source. J Immunol 2013; 190: 881–885.

23.

Glabinski

Tuohy

Ransohoff

. Expression of chemokines RANTES, MIP-1alpha and GRO-alpha correlates with inflammation in acute experimental autoimmune encephalomyelitis. Neuroimmunomodulation 1998; 5: 166–171.

24.

Simpson

Newcombe

Cuzner

. Expression of monocyte chemoattractant protein-1 and other beta-chemokines by resident glia and inflammatory cells in multiple sclerosis lesions. J Neuroimmunol 1998; 84: 238–249.

25.

Prodinger

Bunse

Kruger

. CD11c-expressing cells reside in the juxtavascular parenchyma and extend processes into the glia limitans of the mouse nervous system. Acta Neuropathol 2011; 121: 445–458.

26.

Karpus

Lukacs

McRae

. An important role for the chemokine macrophage inflammatory protein-1 alpha in the pathogenesis of the T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis. J Immunol 1995; 155: 5003–5010.

27.

Bailey-Bucktrout

Caulkins

Goings

. Cutting edge: central nervous system plasmacytoid dendritic cells regulate the severity of relapsing experimental autoimmune encephalomyelitis. J Immunol 2008; 180: 6457–6461.

28.

Schwab

Zozulya

Kieseier

. An imbalance of two functionally and phenotypically different subsets of plasmacytoid dendritic cells characterizes the dysfunctional immune regulation in multiple sclerosis. J Immunol 2010; 184: 5368–5374.

29.

Greter

Heppner

Lemos

. Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat Med 2005; 11: 328–334.

30.

Centonze

Muzio

Rossi

. Inflammation triggers synaptic alteration and degeneration in experimental autoimmune encephalomyelitis. J Neurosci 2009; 29: 3442–3452.

31.

Hebel

Rudolph

Kosak

. IL-1beta and TGF-beta act antagonistically in induction and differentially in propagation of human proinflammatory precursor CD4+ T cells. J Immunol 2011; 187: 5627–5635.

32.

Skarica

Wang

McCadden

. Signal transduction inhibition of APCs diminishes th17 and Th1 responses in experimental autoimmune encephalomyelitis. J Immunol 2009; 182: 4192–4199.

33.

Chiba

Kataoka

Seki

. Fingolimod (FTY720), sphingosine 1-phosphate receptor modulator, shows superior efficacy as compared with interferon-beta in mouse experimental autoimmune encephalomyelitis. Int Immunopharmacol 2011; 11: 366–372.

34.

Kataoka

Sugahara

Shimano

. FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration. Cell Mol Immunol 2005; 2: 439–448.

35.

Ghoreschi

Bruck

Kellerer

. Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells. J Exp Med 2011; 208: 2291–2303.

36.

Wuest

Edwan

Martin

. A role for interleukin-2 trans-presentation in dendritic cell-mediated T cell activation in humans, as revealed by daclizumab therapy. Nat Med 2011; 17: 604–609.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.18 MB

0.20 MB

0.09 MB