Contributions
Abstract: EP1620
Type: ePoster
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Teriflunomide (TF) is an immunmodulatory drug used for treatment of T cell mediated autoimmune diseases e.g. rheumatoid arthritis and multiple sclerosis. Its capacity to inhibit the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) of the de novo pyrimidine synthesis pathway results in a reduced proliferation of activated immune cells. Pharmacological DHODH inhibition via TF interferes with mitochondrial respiration and glycolysis in T cells. Here, we provide first evidence that TF suppresses
T cell proliferation and metabolism in an affinity dependent manner as high affinity T cells were more susceptible towards DHODH inhibition than low affinity T cells. Kinetics of high affinity T cell activation revealed that they increase mitochondrial respiration more rapidly than low affinity T cells in the early phase of activation which explains their enlarged susceptibility towards DHODH inhibition. In an antigen-driven mouse model for central nervous system (CNS) autoimmunity we could illustrate that leflunomide (precursor of TF) treatment results in a preferential reduction of high-affinity T cells and hence in a reduction in mean T cell receptor (TCR) affinities. We therefore hypothesize that DHODH inhibition in vivo results in an altered T cell clonal repertoire, a concept which is further supported by recent data from a clinical trial employing the DHODH inhibitor teriflunomide in relapsing-remitting multiple sclerosis (RRMS) patients (TERIDYNAMIC trial). Taken together, our data suggest that the affinity of the peptide-TCR-interaction directs the mode of energy production in T cells and can hence be specifically targeted via DHODH inhibition.
Disclosure: This study was funded by Sanofi Genzyme, Interdisziplinäres Zentrum für Klinische Forschung (IZKF) Münster, and SFB TR128, Projects A08, and A09.
ME: Speaker honoraria and travel support (Sanofi Genzyme).
LK: Compensation for serving on scientific advisory boards (Genzyme, Novartis); speaker honoraria and travel support (CSL Behring, Merck Serono, Novartis); research support (Biogen Idec, Novartis).
MLindner, MLiebmann, BTG, JB, ASM, PH, GN, SG, KB, MS, DZ: Nothing to disclose.
CG: Speaker honoraria and travel support (Bayer HealthCare, Genzyme).
NS: Travel support (Sanofi Genzyme, Novartis).
SGM: Speaker honoraria, travel support and financial research support (Bayer, Bayer Schering, Biogen Idec, Sanofi Genzyme, Merk Serono, MSD, Novartis, Omniamed, Novo Nordisk, Sanofi, Teva).
TT: Employee of Sanofi Genzyme.
ABO: Speaking, consultancy fees, and/or grant support (Amplimmune, Biogen Idec, Diogenix, Genentech, Genzyme/Sanofi, GSK, Merck/EMD Serono, Novartis, Ono Pharma, Receptos, Roche, Teva Neuroscience).
HW: Compensation for serving on scientific advisory boards (Bayer HealthCare, Biogen Idec, Sanofi Genzyme, Merck Serono, Novartis, Sanofi); speaker honoraria and travel support (Bayer Schering AG, Bayer Vital GmbH, Biogen Idec, CSL Behring, Fresenius Medical Care, Sanofi Genzyme, GSK, GW Pharmaceuticals, Merck Serono, Novartis, Sanofi); compensation as consultant (Biogen Idec, Merck Serono, Novartis, Sanofi).
Abstract: EP1620
Type: ePoster
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Teriflunomide (TF) is an immunmodulatory drug used for treatment of T cell mediated autoimmune diseases e.g. rheumatoid arthritis and multiple sclerosis. Its capacity to inhibit the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) of the de novo pyrimidine synthesis pathway results in a reduced proliferation of activated immune cells. Pharmacological DHODH inhibition via TF interferes with mitochondrial respiration and glycolysis in T cells. Here, we provide first evidence that TF suppresses
T cell proliferation and metabolism in an affinity dependent manner as high affinity T cells were more susceptible towards DHODH inhibition than low affinity T cells. Kinetics of high affinity T cell activation revealed that they increase mitochondrial respiration more rapidly than low affinity T cells in the early phase of activation which explains their enlarged susceptibility towards DHODH inhibition. In an antigen-driven mouse model for central nervous system (CNS) autoimmunity we could illustrate that leflunomide (precursor of TF) treatment results in a preferential reduction of high-affinity T cells and hence in a reduction in mean T cell receptor (TCR) affinities. We therefore hypothesize that DHODH inhibition in vivo results in an altered T cell clonal repertoire, a concept which is further supported by recent data from a clinical trial employing the DHODH inhibitor teriflunomide in relapsing-remitting multiple sclerosis (RRMS) patients (TERIDYNAMIC trial). Taken together, our data suggest that the affinity of the peptide-TCR-interaction directs the mode of energy production in T cells and can hence be specifically targeted via DHODH inhibition.
Disclosure: This study was funded by Sanofi Genzyme, Interdisziplinäres Zentrum für Klinische Forschung (IZKF) Münster, and SFB TR128, Projects A08, and A09.
ME: Speaker honoraria and travel support (Sanofi Genzyme).
LK: Compensation for serving on scientific advisory boards (Genzyme, Novartis); speaker honoraria and travel support (CSL Behring, Merck Serono, Novartis); research support (Biogen Idec, Novartis).
MLindner, MLiebmann, BTG, JB, ASM, PH, GN, SG, KB, MS, DZ: Nothing to disclose.
CG: Speaker honoraria and travel support (Bayer HealthCare, Genzyme).
NS: Travel support (Sanofi Genzyme, Novartis).
SGM: Speaker honoraria, travel support and financial research support (Bayer, Bayer Schering, Biogen Idec, Sanofi Genzyme, Merk Serono, MSD, Novartis, Omniamed, Novo Nordisk, Sanofi, Teva).
TT: Employee of Sanofi Genzyme.
ABO: Speaking, consultancy fees, and/or grant support (Amplimmune, Biogen Idec, Diogenix, Genentech, Genzyme/Sanofi, GSK, Merck/EMD Serono, Novartis, Ono Pharma, Receptos, Roche, Teva Neuroscience).
HW: Compensation for serving on scientific advisory boards (Bayer HealthCare, Biogen Idec, Sanofi Genzyme, Merck Serono, Novartis, Sanofi); speaker honoraria and travel support (Bayer Schering AG, Bayer Vital GmbH, Biogen Idec, CSL Behring, Fresenius Medical Care, Sanofi Genzyme, GSK, GW Pharmaceuticals, Merck Serono, Novartis, Sanofi); compensation as consultant (Biogen Idec, Merck Serono, Novartis, Sanofi).