PMID- 31228713
OWN - NLM
STAT- MEDLINE
DCOM- 20200220
LR  - 20200220
IS  - 2211-0356 (Electronic)
IS  - 2211-0348 (Linking)
VI  - 34
DP  - 2019 Sep
TI  - Fingolimod reduces CXCR4-mediated B cell migration and induces regulatory B 
      cells-mediated anti-inflammatory immune repertoire.
PG  - 29-37
LID - S2211-0348(19)30262-7 [pii]
LID - 10.1016/j.msard.2019.06.016 [doi]
AB  - BACKGROUND: Fingolimod, an oral therapy for patients with relapsing Multiple 
      Sclerosis (MS), traps CC chemokine receptor type 7 (CCR7)-expresssing lymphocytes 
      within lymphoid tissues in the periphery, thereby supposedly reducing the 
      infiltration of pathogenic cells into the central nervous system. Additional 
      immunomodulatory effects of Fingolimod, involving cell function, B and T cells 
      interactions and cross-regulation, have scarcely been studied. The objective of 
      this study was to assess how Fingolimod therapy affects B cells functions, namely 
      cell migration, immunoglobullin production and T cell stimulation. METHODS: B 
      cells from 36 patients with relapsing MS were obtained before and after 3 months 
      Fingolimod therapy, while CD4 T cells were collected pre-treatment. Clinical 
      follow-up was performed for 1 year. For in-vitro validation, Lymphoblastoid 
      cell-lines from 16 patients were cultured with Fingolimod. B cell migration 
      towards C-X-C Motif Chemokine Ligand 12 (CXCL12) was assessed using a transwell 
      system. C-X-C chemokine receptor 4 (CXCR4) expression was assessed by flow 
      cytometry and western blot. Plasma immunoglobullins and Brain-derived 
      Neurotrophic Factor (BDNF) were assessed by ELISA or RT-PCR. Drug effect on 
      interacting co-cultured B and T cells on cytokine profiles and T cell 
      proliferation was explored by flow cytometry. RESULTS: Lymphocyte count reduction 
      did not predict clinical response of patients. Fingolimod therapy reduced CXCR4 
      expression and B cell migration towards CXCL12. No effect was found on 
      immunoglobulins and BDNF. B cells from Fingolimod-treated patients induced a 
      reduction in pro-inflammatory cytokines in T cells, while increased transforming 
      growth factor beta (TGFbeta)(+) B and T cells, and downregulated IL2-secretion from 
      proliferative T cells. CONCLUSIONS: Fingolimod promotes anti-inflammatory 
      cytokine profiles of B and T cells, through induction of regulatory B cells. 
      Reduced B cell migration capacity in Fingolimod-treated patients leading to 
      decreased cerebral inflammatory infiltration, may be part of the mechanism by 
      which Fingolimod reduces disease activity in MS.
CI  - Copyright (c) 2019 Elsevier B.V. All rights reserved.
FAU - Blumenfeld-Kan, Shiri
AU  - Blumenfeld-Kan S
AD  - Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 
      Israel.
FAU - Staun-Ram, Elsebeth
AU  - Staun-Ram E
AD  - Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 
      Israel; Neuroimmunology Unit & Multiple Sclerosis Center, Carmel Medical Center, 
      Haifa, Israel.
FAU - Miller, Ariel
AU  - Miller A
AD  - Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 
      Israel; Neuroimmunology Unit & Multiple Sclerosis Center, Carmel Medical Center, 
      Haifa, Israel. Electronic address: milleras@netvision.net.il.
LA  - eng
PT  - Journal Article
DEP - 20190618
PL  - Netherlands
TA  - Mult Scler Relat Disord
JT  - Multiple sclerosis and related disorders
JID - 101580247
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (CXCL12 protein, human)
RN  - 0 (CXCR4 protein, human)
RN  - 0 (Chemokine CXCL12)
RN  - 0 (IL2 protein, human)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Interleukin-2)
RN  - 0 (Receptors, CXCR4)
RN  - 0 (Transforming Growth Factor beta)
RN  - 7171WSG8A2 (BDNF protein, human)
RN  - G926EC510T (Fingolimod Hydrochloride)
SB  - IM
MH  - Adult
MH  - B-Lymphocytes/*immunology
MH  - Brain-Derived Neurotrophic Factor/metabolism
MH  - Cell Movement/*immunology
MH  - Cell Proliferation
MH  - Chemokine CXCL12/metabolism
MH  - Female
MH  - Fingolimod Hydrochloride/*therapeutic use
MH  - Follow-Up Studies
MH  - Humans
MH  - Immunosuppressive Agents/*therapeutic use
MH  - Inflammation/immunology/therapy
MH  - Interleukin-2/metabolism
MH  - Male
MH  - Multiple Sclerosis, Relapsing-Remitting/immunology/*therapy
MH  - Receptors, CXCR4/*metabolism
MH  - T-Lymphocytes/immunology
MH  - Transforming Growth Factor beta/metabolism
MH  - Treatment Outcome
OTO - NOTNLM
OT  - Bregs
OT  - CXCR4
OT  - Fingolimod
OT  - Migration
OT  - T cell stimulation
EDAT- 2019/06/23 06:00
MHDA- 2020/02/23 06:00
CRDT- 2019/06/23 06:00
PHST- 2019/01/31 00:00 [received]
PHST- 2019/05/24 00:00 [revised]
PHST- 2019/06/16 00:00 [accepted]
PHST- 2019/06/23 06:00 [pubmed]
PHST- 2020/02/23 06:00 [medline]
PHST- 2019/06/23 06:00 [entrez]
AID - S2211-0348(19)30262-7 [pii]
AID - 10.1016/j.msard.2019.06.016 [doi]
PST - ppublish
SO  - Mult Scler Relat Disord. 2019 Sep;34:29-37. doi: 10.1016/j.msard.2019.06.016. 
      Epub 2019 Jun 18.