| dc.description.abstracteng | Multiple sclerosis (MS), the most common autoimmune disorder of the CNS, is characterized by the infiltration of autoreactive inflammatory cells. Nowadays, more and more immune modulating drugs are entering the European market, one of them being teriflunomide. Teriflunomide (A77 1726) is the active metabolite of leflunomide, an anti-inflammatory drug that has been used for a long time in the treatment of rheumatoid arthritis and psoriasis. In MS, teriflunomide has been shown to significantly reduce the relapse rate in clinical studies. The drug is known to be a potent inhibitor of the enzyme DHODH, a mitochondrial enzyme critical for de novo pyrimidine synthesis. The de novo pyrimidine synthesis pathway is essential for the expansion of cells with high-proliferating capacity, and it has been proposed that teriflunomide’s main mechanism of action is an anti-proliferative effect on rapidly dividing cells such as lymphocytes. However, other mechanisms like the inhibition of tyrosine kinases can also play a role.
Therefore, in the present study, we aim to investigate the effect of teriflunomide on CD4+ MBP-reactive T cells both in vitro and in vivo using the experimental autoimmune encephalomyelitis (EAE) model in Lewis rats. Moreover, we aim to understand in which phase of the disease the drug exercises its therapeutic action.
Our in vivo and in vitro data confirmed that the block of proliferation of antigen-specific T cells is the main mechanism of teriflunomide. In addition, this study revealed that teriflunomide interferes with antigen-specific T cell migration during the pre-clinical phase, impairing T cell egression from the lung. At the molecular level, the reduced egression was associated with a differential expression of S1P1 and KLF2, which are important genes in mediating leukocyte egression from lymphoid and non-lymphoid organs.
Furthermore, regarding the time of action, the data indicate that teriflunomide is very effective in preventing disease when administered before clinical onset of EAE, but less effective if administered after onset.
In summary, the data reveal an unexpected mechanism of action of teriflunomide on T cell migration beside the well-known anti-proliferative effect. Additionally, the data reinforce the use of teriflunomide for prophylactic treatment. | de |