Impaired T-cell migration to the CNS under fingolimod and dimethyl fumarate.

Mathias, Amandine; Perriot, Sylvain; Canales, Mathieu; Blatti, Claudia; Gaubicher, Coline; Schluep, Myriam; Engelhardt, Britta; Du Pasquier, Renaud (2017). Impaired T-cell migration to the CNS under fingolimod and dimethyl fumarate. Neurology: Neuroimmunology and Neuroinflammation, 4(6), e401. Wolters Kluwer Health 10.1212/NXI.0000000000000401

[img]
Preview
Text
PMID-29075657.pdf - Published Version
Available under License Publisher holds Copyright.

Download (589kB) | Preview

OBJECTIVE To evaluate the long-term effects of treatments used in MS on the T-cell trafficking profile. METHODS We enrolled 83 patients with MS under fingolimod (FTY), natalizumab (NTZ), dimethyl fumarate (DMF), or other disease-modifying treatments (DMTs). Blood was drawn before treatment onset and up to 36-48 months. The ex vivo expression of CNS-related integrins (α4β1 and αL subunit of LFA-1) and the gut-related integrin (α4β7) was assessed using flow cytometry on CD4+ and CD8+ T cells. The adhesion profiles of CD3+ T cells to specific integrin ligands (vascular cell adhesion molecule-1 [VCAM-1], intercellular adhesion molecule-1 [ICAM-1], and mucosal vascular addressin cell adhesion molecule-1 [MAdCAM-1]) were measured in vitro before and after 12 and 36-48 months. RESULTS NTZ decreased the frequency of α4β1+ and α4β7+ integrin expressing T cells and the binding of these cells to VCAM-1 and MAdCAM-1, respectively. After 12 months, DMF induced a decreased frequency of αLhighCD4+ T cells combined with reduced binding to ICAM-1. By contrast, with FTY, there was a doubling of the frequency of α4β1+ and αLhigh, but a decreased frequency of α4β7+ T cells. Strikingly, the binding of α4β1+, α4β7+, and to a lesser extent of αLhigh T cells to VCAM-1, MAdCAM-1, and ICAM-1, respectively, was decreased at month 12 under FTY treatment. The presence of manganese partially restored the binding of these T cells to VCAM-1 in vitro, suggesting that FTY interferes with integrin activation. CONCLUSIONS In addition to NTZ, DMF and FTY but not other tested DMTs may also decrease T-cell-mediated immune surveillance of the CNS. Whether this mechanism may contribute to the onset of CNS opportunistic infections remains to be shown.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute

UniBE Contributor:

Blatti, Claudia and Engelhardt, Britta

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2332-7812

Publisher:

Wolters Kluwer Health

Language:

English

Submitter:

Ursula Zingg-Zünd

Date Deposited:

16 Jul 2018 10:43

Last Modified:

12 Oct 2018 02:30

Publisher DOI:

10.1212/NXI.0000000000000401

PubMed ID:

29075657

BORIS DOI:

10.7892/boris.111253

URI:

https://boris.unibe.ch/id/eprint/111253

Actions (login required)

Edit item Edit item
Provide Feedback