2. Academic Validation
  3. Targeting deoxycytidine kinase improves symptoms in mouse models of multiple sclerosis

Targeting deoxycytidine kinase improves symptoms in mouse models of multiple sclerosis

  • Immunology. 2023 Jan;168(1):152-169. doi: 10.1111/imm.13569.
Bao Ying Chen 1 2,  Jessica R Salas 1 2,  Alyssa O Trias 1 2,  Arely Perez Rodriguez 1 2,  Jonathan E Tsang 1,  Miriam Guemes 3,  Thuc M Le 1 4,  Zoran Galic 3,  H Michael Shepard 5,  Lawrence Steinman 6,  David A Nathanson 1 4,  Johannes Czernin 1 4,  Owen N Witte 1 7 8,  Caius G Radu 1 4,  Kenneth A Schultz 9,  Peter M Clark 1 2 7
Affiliations

Affiliations

  • 1 Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California, USA.
  • 2 Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, California, USA.
  • 3 Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
  • 4 Ahmanson Translational Imaging Division, University of California, Los Angeles, Los Angeles, California, USA.
  • 5 Enosi Life Sciences, Eugene, Oregon, USA.
  • 6 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
  • 7 Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, California, USA.
  • 8 Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USA.
  • 9 Trethera Corporation, Los Angeles, California, USA.
PMID: 35986643 DOI: 10.1111/imm.13569
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.

Keywords

EAE/MS; autoimmunity; imaging; nucleotide metabolism.

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