Different Susceptibility of T and B Cells to Cladribine Depends On Their Levels of Deoxycytidine Kinase Activity Linked to Activation Status

Federico Carlini, Federico Ivaldi, Francesca Gualandi, Ursula Boschert, Diego Centonze, Giuseppe Matarese, Marco Salvetti, Nicole Kerlero de Rosbo, Antonio Uccelli

Research output: Contribution to journalArticlepeer-review

Abstract

Abstract: Deoxycytidine kinase (dCK) and 5’ deoxynucleotidase (NT5C2) are involved in metabolism of cladribine (2CdA), the immunomodulatory drug for multiple sclerosis; by mediating phosphorylation (activation) or phosphorolysis (deactivation) of 2CdA, respectively, these enzymes promote or prevent its accumulation in the cell, which leads to cell death. In particular, lymphocytes which present with a high intracellular dCK/NT5C2 ratio are more sensitive to 2CdA than other immune cells. We aim at determining if the expression of these enzymes and/or their activity differ in specific progenitor and mature immune cells and are influenced by cellular activation and/or exposure to 2CdA. Flow cytometry analysis showed no difference in dCK/NT5C2 ratio in progenitor and mature immune cells. 2CdA induced apoptosis in stimulated T and B cells and unstimulated B cells. dCK expression was enhanced by 2CdA at mRNA and protein levels in activated T cells and mRNA level in activated B cells. dCK activity, measured through an in-house luminescence release enzyme assay was higher in activated T and B cells, and such an increase was abrogated in activated B cells, but not T cells, upon exposure to 2CdA. These results reveal an important relationship between dCK activity and the effect of 2CdA on B and T cells, according to their activation status. Further study is warranted to evaluate whether dCK activity could, in the future, be a suitable predictive biomarker of lymphocyte response to 2CdA. Graphical Abstract: [InlineMediaObject not available: see fulltext.]

Original languageEnglish
JournalJournal of NeuroImmune Pharmacology
DOIs
Publication statusAccepted/In press - 2021

Keywords

  • 5’ deoxynucleotidase
  • B cells
  • Cladribine
  • Deoxycytidine kinase
  • Multiple sclerosis
  • T cells

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Immunology and Allergy
  • Immunology
  • Pharmacology

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