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

Abstract

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.

<p>Dimethyl Fumarate in the Treatment of Relapsing-Remitting Multiple Sclerosis: Patient Reported Outcomes and Perspectives</p>

“…With the administration of DMF, the number of proinflammatory T cells including CD8+ T cells, CD4+ T cells, CD19+ B cells, CD56 dim NK cells, plasmacytoid DCs, and eosinophils are decreased 22,23. DMF can also reduce in vitro binding of T-cells to adhesion molecules (ie Intercellular adhesion Molecule 1 [ICAM-1]) and therefore prevent immune cell migration 24. In mouse models, DMF decreased the expression of integrin α4, on CD3+ T and B220+ B cells and was shown to decrease the severity and incidence of the clinical scores, as well as delay the onset of experimental autoimmune encephalomyelitis (EAE) 25.…”

Extensive Multiple Sclerosis Reactivation after Switching from Fingolimod to Rituximab

“…Whereas it has been shown that normalization of T cell subsets may take months [ 13 ], the kinetics of B cell reconstitution after cessation of fingolimod has not been studied. In vitro studies suggest that the capacity for T lymphocytes migration across the blood-brain-barrier is suppressed during treatment with fingolimod although the expression of α 4 β 1 integrin is high [ 14 ], which may facilitate enhanced migration upon cessation of fingolimod.…”

Dimethyl fumarate: Regulatory effects on the immune system in the treatment of multiple sclerosis

“…Therefore, the behavior of HBMEC is in contrast to HUVEC (Haarmann et al, ). Mathias et al () showed that DMF decreases the LFA‐1‐mediated binding of T cells to ICAM‐1 and reduces the frequency of αl high CD4 + T cells and prevent the effector T cells to cross the blood‐brain barrier. It is also demonstrated that DMF can downregulate the expression of several chemokines including CXCL9, CXCL10, and CXCL11b that are essential for T‐cell migration (Stoof et al, ).…”

“…Therefore, the behavior of HBMEC is in contrast to HUVEC (Haarmann et al, 2015). Mathias et al (2017) showed that DMF decreases the LFA-1-mediated binding of T cells to ICAM-1 and reduces the frequency of αl high CD4 + T cells and prevent the effector T cells to cross the blood-brain barrier.…”

“…Though several studies have substantiated the clinical effectiveness of DMF in MS treatment the precise mechanism of this process remains elusive. It has been shown that DMF can downregulate the T-and B-cell responses through various mechanisms, such as induction of apoptosis in T cells, selective stimulation of T helper (Th)2 cytokines, and antiinflammatory properties, upregulation of T regulatory (Treg) cells, and inhibition of migration into the injury tissues (de Jong et al, 1996;Gross et al, 2016;Mathias et al, 2017;Treumer, Zhu, Gläser, & Mrowietz, 2003). Recent studies have also indicated that DMF may also exert an immunomodulatory effect on B cells (Claes, Fraussen, Stinissen, Hupperts, & Somers, 2015;Longbrake et al, 2017).…”