Fingolimod reduces circulating tight-junction protein levels and in vitro peripheral blood mononuclear cells migration in multiple sclerosis patients

Giuseppe Marotta,Gianni Masi,Sauro Severi,Chiara Cioni,Maristella Tassi,Pasquale Annunziata

doi:10.1038/s41598-018-33672-9

Giuseppe Marotta, Gianni Masi + Show 4 more

Open Access

https://doi.org/10.1038/s41598-018-33672-9

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Journal: Scientific Reports	Publication Date: Oct 18, 2018
Citations: 12	License type: open-access

Affiliation: University of Siena, Ospedale San Donato

Abstract

There are no data on the effects of fingolimod, an immunomodulatory drug used in treatment of multiple sclerosis (MS), on circulating tight-junction (TJ) protein levels as well as on peripheral blood mononuclear cells (PBMC) migration. Serum TJ protein [occludin (OCLN), claudin-5 (CLN-5) and zonula occludens-1 (ZO-1)] levels, sphingosine-1 phosphate 1 (S1P1) receptor expression on circulating leukocyte populations as well as in vitro PBMC migration were longitudinally assessed in 20 MS patients under 12-months fingolimod treatment and correlated with clinical and magnetic resonance imaging (MRI) parameters. After 12 months of treatment, a significant reduction of mean relapse rate as well as number of active lesions at MRI was found. TJ protein levels significantly decreased and were associated with reduction of S1P1 expression as well as of PBMC in vitro migratory activity. A significant correlation of CLN-5/OCLN ratio with new T2 MRI lesions and a significant inverse correlation of CLN-5/ZO-1 ratio with disability scores were found. These findings support possible in vivo effects of fingolimod on the blood-brain barrier (BBB) functional activity as well as on peripheral cell trafficking that could result in avoiding passage of circulating autoreactive cells into brain parenchyma. Circulating TJ protein levels and respective ratios could be further studied as a novel candidate biomarker of BBB functional status to be monitored in course of fingolimod as well as of other immunomodulatory treatments in MS.

Highlights

In multiple sclerosis (MS), the expansion of activated and autoreactive lymphocyte clones adhering to blood-brain barrier (BBB) endothelium and subsequently migrating into the brain parenchyma is thought to be a fundamental step of cascade of events leading to inflammatory damage to myelin and axons[1]
We demonstrated that treatment with fingolimod is associated with significant reduction of circulating TJ proteins levels contributing to the architecture of BBB
In MS brains, changes in zonula occludens-1 (ZO-1) and OCLN were found in both active lesions and normal-appearing white matter (NAWM)[9] and ZO-1 was found altered in inactive chronic lesions[10]

Summary

Introduction

In multiple sclerosis (MS), the expansion of activated and autoreactive lymphocyte clones adhering to blood-brain barrier (BBB) endothelium and subsequently migrating into the brain parenchyma is thought to be a fundamental step of cascade of events leading to inflammatory damage to myelin and axons[1]. Effects of FTY720 on serum TJ protein levels in MS patients as potential in vivo surrogate marker of BBB repair as well as on peripheral blood mononuclear cells (PBMC) migration. To address these issues, we longitudinally evaluated TJ protein levels in serum of MS patients under FTY720 treatment, measured the S1P1 receptor expression on circulating leukocyte and lymphocyte populations as well as assessed in vitro PBMC migration. We longitudinally evaluated TJ protein levels in serum of MS patients under FTY720 treatment, measured the S1P1 receptor expression on circulating leukocyte and lymphocyte populations as well as assessed in vitro PBMC migration We correlated these findings with clinical and magnetic resonance imaging (MRI) parameters

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