Aubagio (teriflunomide), an approved therapy for relapsing forms of multiple sclerosis (MS), works by shifting the balance between activated subsets of nerve-damaging immune cells to those with immunosuppressive traits, a new study reveals. Further studies to understand how changes in immune cell subsets drive Aubagio’s clinical effectiveness will help in the development of more targeted and effective therapies, the researchers noted. The new study, “Teriflunomide modulates both innate and adaptive immune capacities in multiple sclerosis,” was published in the journal Multiple Sclerosis and Related Disorders. Immune T-cells and B-cells are thought to be involved in the inflammatory attacks that damage the protective myelin sheath surrounding nerve fibers, a hallmark of MS. Aubagio, marketed by Sanofi, has been shown to reduce relapses and delay disability progression in several Phase 3 clinical studies. It works by blocking the activity of an enzyme needed for the accelerated growth of activated T-cells and B-cells. By stopping activated immune cells from replicating, without affecting other cells, Aubagio is assumed to lessen MS-driving inflammation. According to a research team at the University of Michigan Medical School, however, “the exact mechanisms by which [Aubagio] promotes clinical efficacy in RRMS [relapsing-remitting multiple sclerosis] are still not completely understood.” Study sponsored by Sanofi. To learn more, researchers launched a Phase 4 study (NCT03464448), sponsored by Sanofi, to address Aubagio’s mechanism of action. Blood samples were collected from 20 RRMS patients enrolled at the university’s Multiple Sclerosis Center before treatment (baseline) and periodically for up to two years. The analysis examined the therapy’s effects on various subtypes of immune cells. Overall, Aubagio had no significant impact on the total number of T-cells and B-cells after three to seven months of treatment (short-term) or 12 to 28 months (long-term). In a subset of T-cells called regulatory T-cells (Tregs), overall and short-term measurements found an increase in the production of CD39, a protein marker associated with immunosuppression. Tregs can suppress the activity of other immune cells and lessen inflammatory responses, acting to control the immune system. At the same time, treatment reduced the production of the CXCR3 marker associated with the activation of T-helper cells, a subtype of T-cell that stimulates and coordinates immune responses. While the total number of B-cells, immune cells that make and secrete antibodies, showed no significant changes, there was a non-significant trend toward reduction with Aubagio. Naive B-cells — those that have yet to be activated by an immune response — were increased slightly with short-term treatment. In contrast, fully mature (differentiated) memory B-cells that produce antibodies were reduced significantly. Aubagio “shifts balance toward more naïve and less terminally differentiated B cells,” the researchers wrote. On a B-cell subtype, there was a significant early decline in two proteins, CD80 and CD86, known to stimulate T-cell activation. At the later time point, there was still a diminishing trend, which would “mitigate B cells’ ability to activate T cells in [Aubagio]-treated patients with MS,” the team noted. Fewer natural killer cells. Treatment significantly reduced the number of natural killer (NK) cells, a type of white blood cell that can destroy body cells infected with a virus or that have become cancerous. A decreased ratio of two NK subtypes was suggestive of a “[Aubagio]-induced reduction of the pro-inflammatory capacity of NK cells,” they added. Natural killer T-cells, which share properties of both T-cells and NK cells and function like NK cells upon activation, also were reduced significantly with treatment. “Our study shows that [Aubagio] does not significantly reduce T or B cells,” the researchers concluded. “It induces a tolerogenic [immune tolerant] environment by limiting the activation capacity of [blood] pro-inflammatory immune subsets.” “Larger studies may further help determine which subset changes drive the clinical efficacy of RRMS in the search for better targeted treatments,” the researchers added.