Fingolimod Immune Effects Beyond Its Sequestration Ability

Fingolimod is the first orally administered drug approved for the treatment of relapsing–remitting multiple sclerosis (MS). This drug, modulating sphingosine receptors, regulates the trafficking of lymphocytes between primary and secondary lymphoid organs, trapping naïve T cells and central memory T cells in secondary lymphoid organs, without affecting effector memory T cells and therefore without compromising immunosurveillance. Additionally, fingolimod inhibits expression of Th1 and Th17 cytokines and enhances regulatory T-cell differentiation. It also acts on the B arm of immunity through an increased ratio of naïve to memory B cells, higher percentage of plasma cells, and highly increased proportion of transitional B cells as well as additional regulatory subsets. Fingolimod treatment enhances the capacity of regulatory B cells to transmigrate across brain endothelial cells. In fact, patients treated with fingolimod have increased regulatory B-cell frequency in the cerebrospinal fluid. These findings suggest a novel role for fingolimod in MS, by both direct effects and indirect partitioning effects on lymphocytes.