4.8 Article

Teriflunomide Treatment of Multiple Sclerosis Selectively Modulates CD8 Memory T Cells

Journal

FRONTIERS IN IMMUNOLOGY
Volume 12, Issue -, Pages -

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2021.730342

Keywords

multiple sclerosis; teriflunomide; CD8 T cells; CD4 T cells; migration; memory T cells

Categories

Funding

  1. Genzyme Research grant
  2. LabEX IGO program by the National Research Agency via the Investment into the Future program [ANR-11-LABX-0016-01]
  3. BPI France
  4. FP7 VISICORT project - European Unions Seventh Framework Programme for research, technological development and demonstration [602470]

Ask authors/readers for more resources

The study found that 12 months of treatment with teriflunomide in patients with RRMS did not affect B cell or CD4 T cell compartments, but had a specific impact on CD8 T cells, including decreased proliferation and reduced production of inflammatory factors. DHODH inhibition also affected the migratory velocity of memory CD8 T cells.
Background and Objectives 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. 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. Methods High-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. Results We 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 T-REG follicular helper T-FH cell and helper T-H 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 TNF alpha and IFN gamma. 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. Discussion Overall, 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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.8
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available