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

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.

Impact of treatment on cellular immunophenotype in MS

“…Altered levels and/or functional abnormalities in T or B cells have already been reported in patients with MS. 12,[19][20][21] However, previous studies are generally characterized by several limitations, including the focus on particular restricted immune cell subsets, small groups of patients mainly treated with a single DMT, 11,[22][23][24][25][26][27][28][29][30][31] different disease characteristics, lack of inclusion of controls, and difficult standardization of sample processing. 5,13,15,16 In this study, we have undertaken a large multicentric analysis of the immunologic profile of T and B cells in a cohort of 227 patients with MS at different disease stages treated with different DMTs and 82 HCs.…”

Therapeutic and Diagnostic Implications of T Cell Scarring in Celiac Disease and Beyond

“…Different types of T cells have difference in their metabolism, and targeting components of the metabolic machinery can be a way to selectively eliminate T cells [30]. Recently, it was demonstrated that the drug Teriflunimide, an inhibitor of the enzyme dihydroorotate dehydrogenase (DHODH) involved in de novo pyrimidine synthesis, causes selective changes in T cell subset composition and TCR repertoire diversity in patients with relapsing-remitting MS [31]. It was demonstrated that DHODH inhibition mechanistically interfered with oxidative phosphorylation (OXPHOS) and aerobic glycolysis in activated T cells via functional inhibition of complex III of the respiratory chain, and that the effect on T cell proliferation was closely linked to antigen affinity of the T cell clones.…”

Functional relevance of the multi-drug transporter abcg2 on teriflunomide therapy in an animal model of multiple sclerosis

“…However, to elucidate the exact site(s) of action of teri and additional impact of abcg2, further experiments including conditional and chimeric animal models are needed as well as experiments on potential functional redundancy. Furthermore, abcg2-dependent effects on pleiotropic mechanisms of action of teri (i.e., T cell mitochondrial respiration [11];) with emphasis on teri concentrations within cell organelles would be interesting to investigate. However, these aspects were beyond the scope of the current study which set out to investigate if abcg2 has an effect on teri-treatment in vivo.…”

“…Our data indicates that in the animal model, therapeutic modulation of teri efficacy in abcg2-KO mice is not associated with a modulation of peripheral T cell populations. In MS patients treated with teri and in rodents suffering from EAE treated with the respective prodrug leflunomide, it was demonstrated that different T cell populations were selectively affected with a preferential reduction in Th1 effector cells [11]. The differences observed may be explained by different drugs, treatment duration, or therapeutic setting.…”

“…Teri is an oral compound with presumed pleiotropic mechanisms of action. One prominent target appears to be selective inhibition of dihydro-orotate dehydrogenase (DHODH), a key mitochondrial enzyme in the de novo pyrimidine synthesis pathway, leading to a reduction in proliferation of activated T and B lymphocytes [10,11]. Here, we investigated whether modulation of abcg2 influences teri-induced effects in vitro in T cells and in vivo in experimental autoimmune encephalomyelitis (EAE).…”