Teriflunomide Modulates Both Innate and Adaptive Immune Capacities in Multiple Sclerosis

Background: Teriflunomide (TER) (AubagioTM) is an FDA-approved disease-modifying therapy (DMT) for relapsing-remitting multiple sclerosis (RRMS). The mechanism of action of TER is thought to be related to the inhibition of dihydroorotate dehydrogenase (DHODH), a key mitochondrial enzyme in the de novo pyrimidine synthesis pathway required by rapidly dividing lymphocytes. Several large pivotal studies have established the efficacy and safety of TER in patients with RRMS. Despite this, little is known about how the adaptive and innate immune cell subsets are affected by the treatment in patients with MS. Methods: We recruited 20 patients with RRMS who were newly started on TER and performed multicolor flow cytometry and functional assays on peripheral blood samples. A paired t-test was used for the statistical analysis and comparison. Results: Our data showed that TER promoted a tolerogenic environment by shifting the balance between acti-vated pathogenic and naive or immunosuppressive immune cell subsets. In our cohort, TER increased the expression of the immunosuppressive marker CD39 on regulatory T cells (Tregs) while it decreased the expression of the activation marker CXCR3 on CD4+ T helper cells. TER treatment also reduced switched memory (sm) B cells while it increased naive B cells and downregulated the expression of co-stimulatory molecules CD80 and CD86. Additionally, TER reduced the percentage and absolute numbers of natural killer T (NKT) cells, as well as the percentage of natural killer (NK) cells and showed a trend toward reducing the CD56dim NK pathogenic subset. Conclusion: TER promotes the tolerogenic immune response and suppresses the pathogenic immune response in patients with RRMS.