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

Autor:	Klotz L; University Hospital Münster, Department of Neurology with Institute of Translational Neurology, 48149 Münster, Germany. luisa.klotz@ukmuenster.de., Eschborn M; University Hospital Münster, Department of Neurology with Institute of Translational Neurology, 48149 Münster, Germany., Lindner M; University Hospital Münster, Department of Neurology with Institute of Translational Neurology, 48149 Münster, Germany., Liebmann M; University Hospital Münster, Department of Neurology with Institute of Translational Neurology, 48149 Münster, Germany., Herold M; University Hospital Münster, Department of Neurology with Institute of Translational Neurology, 48149 Münster, Germany., Janoschka C; University Hospital Münster, Department of Neurology with Institute of Translational Neurology, 48149 Münster, Germany., Torres Garrido B; University Hospital Münster, Department of Neurology with Institute of Translational Neurology, 48149 Münster, Germany., Schulte-Mecklenbeck A; University Hospital Münster, Department of Neurology with Institute of Translational Neurology, 48149 Münster, Germany., Gross CC; University Hospital Münster, Department of Neurology with Institute of Translational Neurology, 48149 Münster, Germany., Breuer J; University Hospital Münster, Department of Neurology with Institute of Translational Neurology, 48149 Münster, Germany., Hundehege P; University Hospital Münster, Department of Neurology with Institute of Translational Neurology, 48149 Münster, Germany., Posevitz V; University Hospital Münster, Department of Neurology with Institute of Translational Neurology, 48149 Münster, Germany., Pignolet B; CRC-SEP, Neurosciences Department, Toulouse University Hospital and INSERM U1043 - CNRS UMR 5282, Centre de Physiopathologie Toulouse-Purpan, Université Toulouse III, 31300 Toulouse, France., Nebel G; University of Münster, Institute of Molecular Cell Biology, 48149 Münster, Germany., Glander S; University of Münster, Department of Genetic Epidemiology, 48149 Münster, Germany., Freise N; University of Münster, Department of Immunology, 48149 Münster, Germany., Austermann J; University of Münster, Department of Immunology, 48149 Münster, Germany., Wirth T; University Hospital Münster, Department of Neurology with Institute of Translational Neurology, 48149 Münster, Germany., Campbell GR; University of Edinburgh, Centre for Clinical Brain Sciences, EH8 9YL Edinburgh, UK., Schneider-Hohendorf T; University Hospital Münster, Department of Neurology with Institute of Translational Neurology, 48149 Münster, Germany., Eveslage M; University of Münster, Institute of Biostatistics and Clinical Research, 48149 Münster, Germany., Brassat D; CRC-SEP, Neurosciences Department, Toulouse University Hospital and INSERM U1043 - CNRS UMR 5282, Centre de Physiopathologie Toulouse-Purpan, Université Toulouse III, 31300 Toulouse, France., Schwab N; University Hospital Münster, Department of Neurology with Institute of Translational Neurology, 48149 Münster, Germany., Loser K; University Hospital Münster, Department of Dermatology, 48149 Münster, Germany., Roth J; University of Münster, Department of Immunology, 48149 Münster, Germany., Busch KB; University of Münster, Institute of Molecular Cell Biology, 48149 Münster, Germany., Stoll M; University of Münster, Department of Genetic Epidemiology, 48149 Münster, Germany.; Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, 6229 ER Maastricht, Netherlands., Mahad DJ; University of Edinburgh, Centre for Clinical Brain Sciences, EH8 9YL Edinburgh, UK., Meuth SG; University Hospital Münster, Department of Neurology with Institute of Translational Neurology, 48149 Münster, Germany., Turner T; Sanofi Genzyme, Cambridge, MA 02142, USA., Bar-Or A; Center for Neuroinflammation and Experimental Therapeutics and Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Wiendl H; University Hospital Münster, Department of Neurology with Institute of Translational Neurology, 48149 Münster, Germany.; Brain and Mind Centre, Medical Faculty, University of Sydney, Sydney, Camperdown, NSW 2050, Australia.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2019 May 01; Vol. 11 (490).
DOI:	10.1126/scitranslmed.aao5563
Abstrakt:	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. (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze:	MEDLINE
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