Fingolimod increases CD39-expressing regulatory T cells in multiple sclerosis patients

Nathalie Muls; Hong Anh Dang; Christian J M Sindic; Vincent van Pesch

doi:10.1371/journal.pone.0113025

Fingolimod increases CD39-expressing regulatory T cells in multiple sclerosis patients

PLoS One. 2014 Nov 20;9(11):e113025. doi: 10.1371/journal.pone.0113025. eCollection 2014.

Authors

Nathalie Muls¹, Hong Anh Dang¹, Christian J M Sindic², Vincent van Pesch²

Affiliations

¹ Neurochemistry Unit, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium.
² Neurochemistry Unit, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium; Cliniques Universitaires Saint-Luc, Brussels, Belgium.

Abstract

Background: Multiple sclerosis (MS) likely results from an imbalance between regulatory and inflammatory immune processes. CD39 is an ectoenzyme that cleaves ATP to AMP and has been suggested as a novel regulatory T cells (Treg) marker. As ATP has numerous proinflammatory effects, its degradation by CD39 has anti-inflammatory influence. The purpose of this study was to explore regulatory and inflammatory mechanisms activated in fingolimod treated MS patients.

Methods and findings: Peripheral blood mononuclear cells (PBMCs) were isolated from relapsing-remitting MS patients before starting fingolimod and three months after therapy start. mRNA expression was assessed in ex vivo PBMCs. The proportions of CD8, B cells, CD4 and CD39-expressing cells were analysed by flow cytometry. Treg proportion was quantified by flow cytometry and methylation-specific qPCR. Fingolimod treatment increased mRNA levels of CD39, AHR and CYP1B1 but decreased mRNA expression of IL-17, IL-22 and FOXP3 mRNA in PBMCs. B cells, CD4+ cells and Treg proportions were significantly reduced by this treatment, but remaining CD4+ T cells were enriched in FOXP3+ cells and in CD39-expressing Tregs.

Conclusions: In addition to the decrease in circulating CD4+ T cells and CD19+ B cells, our findings highlight additional immunoregulatory mechanisms induced by fingolimod.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antigens, CD / genetics*
Antigens, CD / metabolism
Antigens, CD19 / metabolism
Apyrase / genetics*
Apyrase / metabolism
B-Lymphocytes / metabolism
Basic Helix-Loop-Helix Transcription Factors / genetics
CD4-Positive T-Lymphocytes / metabolism
Cytochrome P-450 CYP1B1 / genetics
Cytokines / metabolism
Fingolimod Hydrochloride / administration & dosage*
Fingolimod Hydrochloride / pharmacology
Gene Expression Regulation / drug effects
Humans
Immunosuppressive Agents / administration & dosage*
Immunosuppressive Agents / pharmacology
Multiple Sclerosis / drug therapy*
Multiple Sclerosis / genetics
Multiple Sclerosis / immunology
Receptors, Aryl Hydrocarbon / genetics
T-Lymphocytes, Regulatory / metabolism*

Substances

AHR protein, human
Antigens, CD
Antigens, CD19
Basic Helix-Loop-Helix Transcription Factors
Cytokines
Immunosuppressive Agents
Receptors, Aryl Hydrocarbon
CYP1B1 protein, human
Cytochrome P-450 CYP1B1
Apyrase
CD39 antigen
Fingolimod Hydrochloride

Grants and funding

This work was financially supported by the Fonds pour la formation à la Recherche dans l'Industrie et dans l'Agriculture, Bayer educational grants (www.fnrs.be/), the Belgian Charcot Foundation (www.fondation-charcot.org/) and the Walloon Region “Désordres Inflammatoires dans les Affections Neurologiques” project (http://recherche-technologie.wallonie.be/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.