title: High-Resolution Expression Profiling of Peripheral Blood CD8+Cells in Patients with Multiple Sclerosis Displays Fingolimod-Induced Immune Cell Redistribution.
abstract: Fingolimod, a sphingosine-1-phosphate (S1P) receptor modulator, is an oral drug approved for the treatment of active relapsing-remitting multiple sclerosis (RRMS). It selectively inhibits the egress of lymphocytes from lymph nodes. We studied the changes in the transcriptome of peripheral blood CD8+cells to unravel the effects at the molecular level during fingolimod therapy. We separated CD8+cells from the blood of RRMS patients before the first dose of fingolimod as well as 24 h and 3 months after the start of therapy. Changes in the expression of coding and non-coding genes were measured with high-density Affymetrix Human Transcriptome Array (HTA) 2.0 microarrays. Differentially expressed genes in response to therapy were identified by t test and fold change and analyzed for their functions and molecular interactions. No gene was expressed at significantly higher or lower levels 24 h after the first administration of fingolimod compared to baseline. However, after 3 months of therapy, 861 transcripts were found to be differentially expressed, including interleukin and chemokine receptors. Some of the genes are associated to the S1P pathway, such as the receptor S1P5 and the kinase MAPK1, which were significantly increased in expression. The fingolimod-induced transcriptome changes reflect a shift in the proportions of CD8+T cell subsets, with CCR7-effector memory T cells being relatively increased in frequency in the blood of fingolimod-treated patients. In consequence, CCR7 mRNA levels were reduced by >80 % and genes involved in T cell activation and lymphocyte cytotoxicity were increased in expression. Gene regulatory programs caused by downstream S1P signaling had only minor effects.
authors.affiliation: Department of Neurology, Division of Neuroimmunology, University of Rostock, Gehlsheimer Str. 20, 18147, Rostock, Germany.
authors.forename: Luisa
authors.initials: L
authors.lastname: Roch
authors.affiliation: Department of Neurology, Division of Neuroimmunology, University of Rostock, Gehlsheimer Str. 20, 18147, Rostock, Germany. michael.hecker@rocketmail.com.|Steinbeis Transfer Center for Proteome Analysis, Schillingallee 70, 18057, Rostock, Germany. michael.hecker@rocketmail.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Hecker
authors.affiliation: Department of Neurology, Division of Neuroimmunology, University of Rostock, Gehlsheimer Str. 20, 18147, Rostock, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Friess
authors.affiliation: Department of Neurology, Division of Neuroimmunology, University of Rostock, Gehlsheimer Str. 20, 18147, Rostock, Germany.
authors.forename: Ines Charlotte
authors.initials: IC
authors.lastname: Angerer
authors.affiliation: Institute of Immunology, University of Rostock, Schillingallee 70, 18057, Rostock, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Koczan
authors.affiliation: Steinbeis Transfer Center for Proteome Analysis, Schillingallee 70, 18057, Rostock, Germany.
authors.forename: Brit
authors.initials: B
authors.lastname: Fitzner
authors.affiliation: Department of Neurology, Division of Neuroimmunology, University of Rostock, Gehlsheimer Str. 20, 18147, Rostock, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Schröder
authors.affiliation: Institute of Immunology, University of Rostock, Schillingallee 70, 18057, Rostock, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Flechtner
authors.affiliation: Steinbeis Transfer Center for Proteome Analysis, Schillingallee 70, 18057, Rostock, Germany.|Institute of Immunology, University of Rostock, Schillingallee 70, 18057, Rostock, Germany.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Thiesen
authors.affiliation: Department of Neurology, Division of Neuroimmunology, University of Rostock, Gehlsheimer Str. 20, 18147, Rostock, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Meister
authors.affiliation: Department of Neurology, Division of Neuroimmunology, University of Rostock, Gehlsheimer Str. 20, 18147, Rostock, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Winkelmann
authors.affiliation: Department of Neurology, Division of Neuroimmunology, University of Rostock, Gehlsheimer Str. 20, 18147, Rostock, Germany.
authors.forename: Uwe Klaus
authors.initials: UK
authors.lastname: Zettl
mesh_terms: D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D016207:Cytokines / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology*; D010641:Phenotype; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D016207:Cytokines; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
keywords: CD8+ T cells; Fingolimod; Peripheral blood; Relapsing-remitting multiple sclerosis; Sphingosine-1-phosphate; Transcriptome profiling