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Evonuk, Kirsten Scarlett; Wang, Sen; Mattie, Josh; Cracchiolo, C. J.; Mager, Reine; Ferenčić, Željko; Sprague, Ethan; Carrier, Brandon; Schofield, Kai; Martinez, Evelyn; Stewart, Zachary; Petrosino, Tara; Johnson, Gregory Andrew; Yusuf, Isharat; Plaisted, Warren; Naiman, Zachary; Delp, Timothy; Carter, Laura; Marušić, Suzana

Bruton’s tyrosine kinase inhibition reduces disease severity in a model of secondary progressive autoimmune demyelination

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  • Medientyp: E-Artikel
  • Titel: Bruton’s tyrosine kinase inhibition reduces disease severity in a model of secondary progressive autoimmune demyelination
  • Beteiligte: Evonuk, Kirsten Scarlett; Wang, Sen; Mattie, Josh; Cracchiolo, C. J.; Mager, Reine; Ferenčić, Željko; Sprague, Ethan; Carrier, Brandon; Schofield, Kai; Martinez, Evelyn; Stewart, Zachary; Petrosino, Tara; Johnson, Gregory Andrew; Yusuf, Isharat; Plaisted, Warren; Naiman, Zachary; Delp, Timothy; Carter, Laura; Marušić, Suzana
  • Erschienen: Springer Science and Business Media LLC, 2023
  • Erschienen in: Acta Neuropathologica Communications
  • Sprache: Englisch
  • DOI: 10.1186/s40478-023-01614-w
  • ISSN: 2051-5960
  • Schlagwörter: Cellular and Molecular Neuroscience ; Neurology (clinical) ; Pathology and Forensic Medicine
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  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>Bruton’s tyrosine kinase (BTK) is an emerging target in multiple sclerosis (MS). Alongside its role in B cell receptor signaling and B cell development, BTK regulates myeloid cell activation and inflammatory responses. Here we demonstrate efficacy of BTK inhibition in a model of secondary progressive autoimmune demyelination in Biozzi mice with experimental autoimmune encephalomyelitis (EAE). We show that late in the course of disease, EAE severity could not be reduced with a potent relapse inhibitor, FTY720 (fingolimod), indicating that disease was relapse-independent. During this same phase of disease, treatment with a BTK inhibitor reduced both EAE severity and demyelination compared to vehicle treatment. Compared to vehicle treatment, late therapeutic BTK inhibition resulted in fewer spinal cord-infiltrating myeloid cells, with lower expression of CD86, pro-IL-1β, CD206, and Iba1, and higher expression of Arg1, in both tissue-resident and infiltrating myeloid cells, suggesting a less inflammatory myeloid cell milieu. These changes were accompanied by decreased spinal cord axonal damage. We show similar efficacy with two small molecule inhibitors, including a novel, highly selective, central nervous system-penetrant BTK inhibitor, GB7208. These results suggest that through lymphoid and myeloid cell regulation, BTK inhibition reduced neurodegeneration and disease progression during secondary progressive EAE.</jats:p>
  • Zugangsstatus: Freier Zugang