Teriflunomide Treatment of Multiple Sclerosis Selectively Modulates CD8 Memory T Cells.

Gaëlle Tilly,Sandrine Wiertlewski,Sophie Brouard,Marion Cadoux,David Laplaud,Claire Pecqueur,Jérémy Morille,Nicolas Degauque,Alexandra Garcia

doi:10.3389/fimmu.2021.730342

Abstract

Background and ObjectivesInhibition of de novo pyrimidine synthesis in proliferating T and B lymphocytes by teriflunomide, a pharmacological inhibitor of dihydroorotate dehydrogenase (DHODH), has been shown to be an effective therapy to treat patients with MS in placebo-controlled phase 3 trials. Nevertheless, the underlying mechanism contributing to the efficacy of DHODH inhibition has been only partially elucidated. Here, we aimed to determine the impact of teriflunomide on the immune compartment in a longitudinal high-dimensional follow-up of patients with relapse-remitting MS (RRMS) treated with teriflunomide.MethodsHigh-dimensional spectral flow cytometry was used to analyze the phenotype and the function of innate and adaptive immune system of patients with RRMS before and 12 months after teriflunomide treatment. In addition, we assessed the impact of teriflunomide on the migration of memory CD8 T cells in patients with RRMS, and we defined patient immune metabolic profiles.ResultsWe found that 12 months of treatment with teriflunomide in patients with RRMS does not affect the B cell or CD4 T cell compartments, including regulatory TREG follicular helper TFH cell and helper TH cell subsets. In contrast, we observed a specific impact of teriflunomide on the CD8 T cell compartment, which was characterized by decreased homeostatic proliferation and reduced production of TNFα and IFNγ. Furthermore, we showed that DHODH inhibition also had a negative impact on the migratory velocity of memory CD8 T cells in patients with RRMS. Finally, we showed that the susceptibility of memory CD8 T cells to DHODH inhibition was not related to impaired metabolism.DiscussionOverall, these findings demonstrate that the clinical efficacy of teriflunomide results partially in the specific susceptibility of memory CD8 T cells to DHODH inhibition in patients with RRMS and strengthens active roles for these T cells in the pathophysiological process of MS.

Highlights

The selective and reversible inhibition of dihydroorotate dehydrogenase (DHODH), a key mitochondrial enzyme in the de novo pyrimidine synthesis pathway, by teriflunomide has been shown to be a safe and effective strategy to treat patients with multiple sclerosis (MS)
We investigated the impact of DHODH inhibition in patients with relapse-remitting MS (RRMS) before and 12 months after treatment using high-dimensional flow cytometry to characterize the immune system as a whole
Using high-dimensional flow cytometry, we investigated the impact of DHODH inhibition in patients with RRMS before and 12 months posttreatment

Summary

Introduction

The selective and reversible inhibition of dihydroorotate dehydrogenase (DHODH), a key mitochondrial enzyme in the de novo pyrimidine synthesis pathway, by teriflunomide has been shown to be a safe and effective strategy to treat patients with multiple sclerosis (MS). A decrease in only the frequency of CD45RA+ effector memory (TEMRA) CD4 T cells and plasmablasts has been reported for patients with MS after 6 months of treatment, while the frequency of other immune cells, including CD8 T cells, remained similar before and after DHODH inhibition [9]. Inhibition of de novo pyrimidine synthesis in proliferating T and B lymphocytes by teriflunomide, a pharmacological inhibitor of dihydroorotate dehydrogenase (DHODH), has been shown to be an effective therapy to treat patients with MS in placebo-controlled phase 3 trials. We aimed to determine the impact of teriflunomide on the immune compartment in a longitudinal high-dimensional follow-up of patients with relapse-remitting MS (RRMS) treated with teriflunomide

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Conclusion