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Targeting deoxycytidine kinase improves symptoms in mouse models of multiple sclerosis.
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.
Affiliation
  • Chen BY; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California, USA.
  • Salas JR; Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, California, USA.
  • Trias AO; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California, USA.
  • Perez Rodriguez A; Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, California, USA.
  • Tsang JE; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California, USA.
  • Guemes M; Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, California, USA.
  • Le TM; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California, USA.
  • Galic Z; Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, California, USA.
  • Shepard HM; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California, USA.
  • Steinman L; Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
  • Nathanson DA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California, USA.
  • Czernin J; Ahmanson Translational Imaging Division, University of California, Los Angeles, Los Angeles, California, USA.
  • Witte ON; Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
  • Radu CG; Enosi Life Sciences, Eugene, Oregon, USA.
  • Schultz KA; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
  • Clark PM; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California, USA.
Immunology ; 168(1): 152-169, 2023 01.
Article in En | MEDLINE | ID: mdl-35986643
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.
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Full text: 1 Database: MEDLINE Main subject: Encephalomyelitis, Autoimmune, Experimental / Multiple Sclerosis Type of study: Diagnostic_studies Limits: Animals Language: En Journal: Immunology Year: 2023 Type: Article Affiliation country: United States
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Full text: 1 Database: MEDLINE Main subject: Encephalomyelitis, Autoimmune, Experimental / Multiple Sclerosis Type of study: Diagnostic_studies Limits: Animals Language: En Journal: Immunology Year: 2023 Type: Article Affiliation country: United States