Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects
| Autor: | Maren Lindner, Béatrice Pignolet, David Brassat, Petra Hundehege, Maria Eveslage, Melanie Eschborn, Johanna Breuer, Luisa Klotz, Karin Loser, Andreas Schulte-Mecklenbeck, Sven G. Meuth, Judith Austermann, Catharina C. Gross, Nicole Freise, Karin B. Busch, Nicholas Schwab, Giulia Nebel, Tilman Schneider-Hohendorf, Timothy J. Turner, Vilmos Posevitz, Heinz Wiendl, Marie Liebmann, Amit Bar-Or, Martin Herold, Shirin Glander, Belén Torres Garrido, Johannes Roth, Claudia Janoschka, Timo Wirth, Graham R. Campbell, Don J. Mahad, Monika Stoll |
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| Přispěvatelé: | Biochemie, RS: FHML MaCSBio, RS: CARIM - R1 - Thrombosis and haemostasis, RS: Carim - B01 Blood proteins & engineering, University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Edinburgh, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University [Maastricht], Sanofi Genzyme, Perelman School of Medicine, University of Pennsylvania, The University of Sydney, Pistre, Karine |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
MESH: Dihydroorotate Dehydrogenase
[SDV]Life Sciences [q-bio] T-Lymphocytes Respiratory chain Dihydroorotate Dehydrogenase Hydroxybutyrates Lymphocyte Activation MESH: Electron Transport Complex III / metabolism Oxidative Phosphorylation chemistry.chemical_compound Electron Transport Complex III LEFLUNOMIDE Teriflunomide MESH: Animals MESH: Hydroxybutyrates Chemistry MESH: Gene Expression Regulation / drug effects MESH: Aerobiosis / drug effects General Medicine Aerobiosis Cell biology Mitochondria [SDV] Life Sciences [q-bio] medicine.anatomical_structure MESH: Crotonates / pharmacology Crotonates Pyrimidine metabolism [SDV.IMM]Life Sciences [q-bio]/Immunology Glycolysis TCR Oxidoreductases Acting on CH-CH Group Donors Multiple Sclerosis [SDV.IMM] Life Sciences [q-bio]/Immunology AVIDITY MATURATION Toluidines T cell Cell Respiration Receptors Antigen T-Cell MESH: Cell Proliferation / drug effects MESH: Crotonates / therapeutic use Immune system Multiple Sclerosis Relapsing-Remitting Antigen Nitriles medicine Animals Humans MESH: Glycolysis / drug effects NEGATIVE SELECTION Cell Proliferation MESH: Lymphocyte Subsets / immunology MESH: Cell Respiration / drug effects MESH: Humans Cell growth MESH: Mitochondria / drug effects MESH: Lymphocyte Activation / drug effects Lymphocyte Subsets MESH: Lymphocyte Subsets / drug effects RHEUMATOID-ARTHRITIS MESH: Mitochondria / metabolism Gene Expression Regulation Dihydroorotate dehydrogenase Energy Metabolism MESH: Energy Metabolism / drug effects |
| Zdroj: | Klotz, L, Eschborn, M, Lindner, M, Liebmann, M, Herold, M, Janoschka, C, Torres Garrido, B, Schulte-Mecklenbeck, A, Gross, C C, Breuer, J, Hundehege, P, Posevitz, V, Pignolet, B, Nebel, G, Glander, S, Freise, N, Austermann, J, Wirth, T, Campbell, G R, Schneider-Hohendorf, T, Eveslage, M, Brassat, D, Schwab, N, Loser, K, Roth, J, Busch, K B, Stoll, M, Mahad, D J, Meuth, S G, Turner, T, Bar-Or, A & Wiendl, H 2019, ' Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects ', Science Translational Medicine, vol. 11, no. 490, eaao5563 . https://doi.org/10.1126/scitranslmed.aao5563 Science Translational Medicine, 11(490):5563. American Association for the Advancement of Science Science Translational Medicine Science Translational Medicine, 2019, 11 (490), ⟨10.1126/scitranslmed.aao5563⟩ |
| ISSN: | 1946-6234 1946-6242 |
| DOI: | 10.1126/scitranslmed.aao5563 |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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