Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 11, Issue 490, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aao5563
Keywords
-
Categories
Funding
- Interdisziplinares Zentrum fur Klinische Forschung (IZKF), Munster [LK2/015/14]
- Deutsche Forschungsgemeinschaft (DFG) [SFB TR128, SFB 1009, WI 1722/12-1]
- Sanofi Genzyme
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available