Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects

Sci Transl Med. 2019 May 1;11(490):eaao5563. doi: 10.1126/scitranslmed.aao5563.

Abstract

Interference with immune cell proliferation represents a successful treatment strategy in T cell-mediated autoimmune diseases such as rheumatoid arthritis and multiple sclerosis (MS). One prominent example is pharmacological inhibition of dihydroorotate dehydrogenase (DHODH), which mediates de novo pyrimidine synthesis in actively proliferating T and B lymphocytes. Within the TERIDYNAMIC clinical study, we observed that the DHODH inhibitor teriflunomide caused selective changes in T cell subset composition and T cell receptor repertoire diversity in patients with relapsing-remitting MS (RRMS). In a preclinical antigen-specific setup, DHODH inhibition preferentially suppressed the proliferation of high-affinity T cells. Mechanistically, DHODH inhibition interferes with oxidative phosphorylation (OXPHOS) and aerobic glycolysis in activated T cells via functional inhibition of complex III of the respiratory chain. The affinity-dependent effects of DHODH inhibition were closely linked to differences in T cell metabolism. High-affinity T cells preferentially use OXPHOS during early activation, which explains their increased susceptibility toward DHODH inhibition. In a mouse model of MS, DHODH inhibitory treatment resulted in preferential inhibition of high-affinity autoreactive T cell clones. Compared to T cells from healthy controls, T cells from patients with RRMS exhibited increased OXPHOS and glycolysis, which were reduced with teriflunomide treatment. Together, these data point to a mechanism of action where DHODH inhibition corrects metabolic disturbances in T cells, which primarily affects profoundly metabolically active high-affinity T cell clones. Hence, DHODH inhibition may promote recovery of an altered T cell receptor repertoire in autoimmunity.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aerobiosis / drug effects
  • Animals
  • Cell Proliferation / drug effects
  • Cell Respiration / drug effects
  • Crotonates / pharmacology
  • Crotonates / therapeutic use*
  • Electron Transport Complex III / metabolism
  • Energy Metabolism / drug effects
  • Gene Expression Regulation / drug effects
  • Glycolysis / drug effects
  • Humans
  • Lymphocyte Activation / drug effects
  • Lymphocyte Subsets / drug effects
  • Lymphocyte Subsets / immunology
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Multiple Sclerosis / drug therapy*
  • Multiple Sclerosis / genetics
  • Multiple Sclerosis / immunology*
  • Multiple Sclerosis / pathology
  • Multiple Sclerosis, Relapsing-Remitting / immunology
  • Oxidative Phosphorylation / drug effects
  • Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors
  • Oxidoreductases Acting on CH-CH Group Donors / metabolism
  • Receptors, Antigen, T-Cell / metabolism
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • Toluidines / pharmacology
  • Toluidines / therapeutic use*

Substances

  • Crotonates
  • Receptors, Antigen, T-Cell
  • Toluidines
  • teriflunomide
  • Oxidoreductases Acting on CH-CH Group Donors
  • dihydroorotate dehydrogenase
  • Electron Transport Complex III