Protective Effect of Bruton Tyrosine Kinase Inhibitor in Murine Model of Chronic Demyelination

Abstract

Background Ibrutinib, a Bruton Tyrosine Kinase inhibitor (iBTK), binds with target protein to arrest B-cell development and decrease microglia activation. Considering the emerging role of B and microglial cells in multiple sclerosis (MS) pathology, BTK inhibition is being considered a novel therapeutic strategy. Objective To investigate the effects of Ibrutinib on the disease pathology and clinical disability of the Theiler’s Murine Encephalomyelitis Virus (TMEV) mouse model of MS. Methods Twenty-six TMEV injected mice were treated at 1-month post induction (mPI) with iBTK (n = 13) or vehicle control (n = 13). Clinical disability, weight and rotarod performance was recorded at 1, 2, 3, and 5 mPI. Histology analysis was performed on spinal cord tissue at 3 and 5 mPI with Iba1 staining. ELISA was conducted to confirm TMEV infection. CD19 expressing B-cell fraction of peripheral blood mono-nuclear cells was quantified. Results At functional level, iBTK showed lower clinical worsening (p < 0.001), higher body weights (p = 0.033) and longer rotarod retention (p = 0.048), compared to the vehicle treatment arm. CD19 expressing B-cell fraction was reduced in iBTK (6.65 ± 1.92%) relative to vehicle (12.51 ± 2.34%) (p = 0.043). Furthermore, CD3 density was lower both in grey matter (GM) (p = 0.013) and white matter (WM) (p = 0.025) lesions in the iBTK. IBTK presented lower density and activation of Iba1 positive cells within the spinal cord (p = 0.025). Additionally, at 3 mPI TMEV, spinal cord lesion area was lower in spinal WM (p = 0.016) and was trending lower in GM (p = 0.077) in iBTK. Conclusions Treatment with iBTK decreased B-cell fraction and microglia activation in TMEV model of MS, resulting in lower lesion burden and reduced clinical disability, body weight loss and motor dysfunction. It will be relevant to assess iBTK’s effect on neuroimaging measures of immune cell infiltration and the presence of neurodegeneration in the CNS and characterize resulting immune cell changes in future studies.