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

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

Author information

1
University Hospital Münster, Department of Neurology with Institute of Translational Neurology, 48149 Münster, Germany. luisa.klotz@ukmuenster.de.
2
University Hospital Münster, Department of Neurology with Institute of Translational Neurology, 48149 Münster, Germany.
3
CRC-SEP, Neurosciences Department, Toulouse University Hospital and INSERM U1043 - CNRS UMR 5282, Centre de Physiopathologie Toulouse-Purpan, Université Toulouse III, 31300 Toulouse, France.
4
University of Münster, Institute of Molecular Cell Biology, 48149 Münster, Germany.
5
University of Münster, Department of Genetic Epidemiology, 48149 Münster, Germany.
6
University of Münster, Department of Immunology, 48149 Münster, Germany.
7
University of Edinburgh, Centre for Clinical Brain Sciences, EH8 9YL Edinburgh, UK.
8
University of Münster, Institute of Biostatistics and Clinical Research, 48149 Münster, Germany.
9
University Hospital Münster, Department of Dermatology, 48149 Münster, Germany.
10
Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, 6229 ER Maastricht, Netherlands.
11
Sanofi Genzyme, Cambridge, MA 02142, USA.
12
Center for Neuroinflammation and Experimental Therapeutics and Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
13
Brain and Mind Centre, Medical Faculty, University of Sydney, Sydney, Camperdown, NSW 2050, Australia.

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.

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