1. Targeting deoxycytidine kinase improves symptoms in mouse models of multiple sclerosis
- Author
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Chen, Bao Ying, Salas, Jessica R, Trias, Alyssa O, Rodriguez, Arely Perez, Tsang, Jonathan E, Guemes, Miriam, Le, Thuc M, Galic, Zoran, Shepard, H Michael, Steinman, Lawrence, Nathanson, David A, Czernin, Johannes, Witte, Owen N, Radu, Caius G, Schultz, Kenneth A, and Clark, Peter M
- Subjects
Biomedical and Clinical Sciences ,Immunology ,Autoimmune Disease ,Neurodegenerative ,Neurosciences ,Brain Disorders ,Multiple Sclerosis ,2.1 Biological and endogenous factors ,Aetiology ,Inflammatory and immune system ,Neurological ,Animals ,Mice ,Deoxycytidine Kinase ,Encephalomyelitis ,Autoimmune ,Experimental ,Lymphocytes ,Disease Models ,Animal ,Mice ,Inbred C57BL ,autoimmunity ,EAE ,MS ,imaging ,nucleotide metabolism ,EAE/MS ,Paediatrics and Reproductive Medicine - Abstract
Multiple sclerosis (MS) is an autoimmune disease driven by lymphocyte activation against myelin autoantigens in the central nervous system leading to demyelination and neurodegeneration. The deoxyribonucleoside salvage pathway with the rate-limiting enzyme deoxycytidine kinase (dCK) captures extracellular deoxyribonucleosides for use in intracellular deoxyribonucleotide metabolism. Previous studies have shown that deoxyribonucleoside salvage activity is enriched in lymphocytes and required for early lymphocyte development. However, specific roles for the deoxyribonucleoside salvage pathway and dCK in autoimmune diseases such as MS are unknown. Here we demonstrate that dCK activity is necessary for the development of clinical symptoms in the MOG35-55 and MOG1-125 experimental autoimmune encephalomyelitis (EAE) mouse models of MS. During EAE disease, deoxyribonucleoside salvage activity is elevated in the spleen and lymph nodes. Targeting dCK with the small molecule dCK inhibitor TRE-515 limits disease severity when treatments are started at disease induction or when symptoms first appear. EAE mice treated with TRE-515 have significantly fewer infiltrating leukocytes in the spinal cord, and TRE-515 blocks activation-induced B and T cell proliferation and MOG35-55 -specific T cell expansion without affecting innate immune cells or naïve T and B cell populations. Our results demonstrate that targeting dCK limits symptoms in EAE mice and suggest that dCK activity is required for MOG35-55 -specific lymphocyte activation-induced proliferation.
- Published
- 2023