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

To evaluate the long-term effects of treatments used in MS on the T-cell trafficking profile.

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 α_L 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.

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 α_L^highCD4⁺ T cells combined with reduced binding to ICAM-1. By contrast, with FTY, there was a doubling of the frequency of α4β1⁺ and α_L^high, but a decreased frequency of α4β7⁺ T cells. Strikingly, the binding of α4β1⁺, α4β7⁺, and to a lesser extent of α_L^high 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.

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.