Abstract

Introduction: Natalizumab (NAT) is an effective treatment for relapsing remitting multiple sclerosis (RRMS), as it makes the blood-brain-barrier impenetrable by binding to the α4integrin subunit. The objectives of our study were to find new peripheral mechanisms of action of NAT and new biomarkers of treatment response.

Material and Methods: We prospectively assessed the serum levels of 15 cytokines from the Th17 Cytokine Panel using Bio-plex Pro Human in a group of 29 RRMS patients treated with NAT and 29 healthy subjects (HS) at inclusion and after 8 months of NAT treatment. For each patient, demographic data, number of relapses and Expanded Disability Status Scale (EDSS) were collected and compared with the initial and final values of each cytokine. Moreover, the Th17/Treg shift was assessed using the interleukine (IL)-17F/IL-10 ratio and the cytokine signature (the sum of all the cytokines). Advanced statistical analysis was used.

Results: RRMS patients had significantly lower serum levels of IL-23, IL-17F, IL-1β and IL-31 compared to HS. Serum sCD40L, IL-17F, IL-31 and cytokine signature levels significantly decreased after 8 months of NAT treatment. Positively correlations were found between the relapse number and IL- 17F, IL-1β, IL-31 serum levels and between EDSS and tumor necrotic factor-α, IL-1β and IL-17/IL-10 serum levels. IL-10 serum levels correlated negatively with the EDSS score.

Conclusion: In evaluating the mode of action of NAT, it is important to determine the value of each cytokine, the Th17/Treg shift and the cytokine signature. NAT significantly decreased peripheral serum levels of some pro-inflammatory cytokines as a novel mechanism of action. IL-17F, sCD40L and IL-31 were the best biomarkers to assess the effectiveness of NAT.

Keywords: Blood brain barrier, cytokine, mechanism of action, multiple sclerosis, natalizumab, RRMS.

Graphical Abstract