Targeting deoxycytidine kinase improves symptoms in mouse models of multiple sclerosis

• Published in: Immunology 2023-01, Vol.168 (1), p.152-169
• Main Authors: Chen, Bao Ying, Salas, Jessica R., Trias, Alyssa O., Perez Rodriguez, Arely, 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., Clark, Peter M.
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Autoantigens; Autoimmune diseases; autoimmunity; Cell activation; Cell proliferation; Central nervous system; Demyelination; Deoxycytidine kinase; Deoxycytidine Kinase - genetics; Disease; Disease Models, Animal; EAE/MS; Encephalomyelitis, Autoimmune, Experimental; Experimental allergic encephalomyelitis; imaging; Immune system; Kinases; Leukocytes; Lymph nodes; Lymphocytes; Lymphocytes - metabolism; Lymphocytes T; Metabolism; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Myelin; Neurodegeneration; nucleotide metabolism; Signs and symptoms; Spinal cord
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1111/imm.13569

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. Identifying new targetable proteins in multiple sclerosis could improve the treatment of this disease. Deoxycytidine kinase is the rate‐limiting enzyme in the deoxyribonucleoside salvage pathway. We show that deoxycytidine kinase activity is upregulated in the lymph nodes and spleen in models of multiple sclerosis. Treating these models prophylactically or therapeutically with the dCK inhibitor TRE‐515 limits disease. TRE‐515 selectively blocks T and B cell activation‐induced proliferation without affecting other aspects of the immune system including naïve T and B cells or innate immune cells. Our results suggest deoxycytidine kinase as a potential target for the treatment of multiple sclerosis.