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Transcriptional modulation induced by fingolimod treatment in relapsing remitting multiple sclerosis patients
Author(s): ,
G. Sferruzza
Affiliations:
CNS Inflammatory Unit & INSPE; Neurology, San Raffaele Scientific Institute
,
F. Clarelli
Affiliations:
CNS Inflammatory Unit & INSPE, San Raffaele Scientific Insitute, Milano
,
P. Provero
Affiliations:
Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin; 4Center for Translational Genomics and BioInformatics, San Raffaele Scientific Insitute, Milan
,
L. Ferrè
Affiliations:
CNS Inflammatory Unit & INSPE, San Raffaele Scientific Insitute, Milano; Neurology, San Raffaele Scientific Insitute, Milano
,
E. Mascia
Affiliations:
CNS Inflammatory Unit & INSPE, San Raffaele Scientific Insitute, Milano
,
L. Moiola
Affiliations:
Neurology, San Raffaele Scientific Insitute, Milano
,
V. Martinelli
Affiliations:
Neurology, San Raffaele Scientific Insitute, Milano
,
G. Comi
Affiliations:
Neurology, San Raffaele Scientific Insitute, Milano
,
F. Martinelli Boneschi
Affiliations:
Department of Neurology, IRCCS Policlinico San Donato, San Donato Milanese; Department of Biomedical Sciences for Health, University of Milan, Milano, Italy
F. Esposito
Affiliations:
CNS Inflammatory Unit & INSPE, San Raffaele Scientific Insitute, Milano; Neurology, San Raffaele Scientific Insitute, Milano
ECTRIMS Online Library. Sferruzza G. Oct 12, 2018; 229049; P1209
Giacomo Sferruzza
Giacomo Sferruzza
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Abstract: P1209

Type: Poster Sessions

Abstract Category: Therapy - Immunomodulation/Immunosuppression

Introduction: fingolimod (FTY) is a second-line drug approved for Relapsing Remitting Multiple Sclerosis. It is known to prevent lymphocyte egress outside lymph nodes, reducing peripheral lymphocytes counts. We investigated transcriptional changes induced by the drug in B and T lymphocytes in order to better elucidate its mechanism of action at the molecular and pathway levels.
Materials and methods: 24 RRMS patients were sampled at baseline and after 6 months of FTY treatment. CD3+ T cells and CD20+ B cells were sorted with MACS MicroBeads system and RNA sequencing performed using Illumina NextSeq500 platform. Differentially expressed genes (DEGs) were identified for each cell type and genes modulated by FTY (fold change [FC]>2 or FC< 0.5 and false discovery rate [FDR]< 5%) were considered for a pathway analysis based on KEGG database.
Subpaths activation state was also tested using MinePath tool. We performed network analysis on cell-specific interactomes, followed by centrality-based analysis to elicit key genes.
Results: a marked up-regulation was observed in both T and B lymphocytes (313 up- and 240 down-regulated genes in T cells; 400 up- and 104 down-regulated genes in B cells). Most of the DEGs resulted implicated in cell migration or immune-related functions, largely confirming results from previous microarray-based studies: among them CX3CR1 was strongly up-regulated (padjusted=6.4x10-26, FC=5.96) and CCR7 was down-regulated in both cell types (padjusted=5.4x10-31, FC=0.18). Pathway and subpaths analyses confirmed an involvement of processes related with immune function and cell migration, with particular involvement of RAP1A, RAC1 and ZAP70 as nodes of several subpaths activated at 6 months. Network analysis elicited hub genes like CD44 involved in cell migration and several down-regulated hubs related with ribosome function.
Conclusions: Our data suggest that FTY induces major transcriptional changes in genes with immune and cell migration functions associated with a down-regulation of several central hubs related with ribosome function; this modulation is shared between T and B lymphocytes.
Disclosure: G. Sferruzza: nothing to disclose
F. Clarelli: nothing to disclose.
P.Provero: nothing to disclose.
L. Ferre': nothing to disclose.
E. Mascia: nothing to disclose.
L. Moiola received honoraria for speaking at meetings or for attending to advisory board from Sanofi-Genzyme, Biogen-Idec, Novartis and TEVA.
V. Martinelli has received honoraria for consulting and speaking activities from Biogen-Idec, Merck, Bayer, TEVA, Novartis and Genzyme.
G. Comi has received compensation for consulting services with the following companies: Novartis, Teva, Sanofi, Genzyme, Merck, Biogen, Excemed, Roche, Almirall, Chugai, Receptos, Forward Pharma and compensation for speaking activities from Novartis, Teva, Sanofi, Genzyme, Merk, Biogen, Excemed, Roche.
F. Martinelli Boneschi has received compensation for activities with Teva Neuroscienze as speaker and/or advisor.
F. Esposito received honoraria from Almirall and Genzyme.

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