Ibrutinib is a Bruton Tyrosine Kinase inhibitor (iBTK) treatment which binds with target protein to arrest B cell development and decrease microglia activation. The Theiler’s Murine Encephalomyelitis Virus (TMEV) infection induces an immune-mediated chronic multiple sclerosis (MS) like disease of the central nervous system. Hence, we hypothesized that iBTK treatment will suppress the TMEV pathology.
We studied clinical disability, motor learning and spinal cord lesion load in TMEV-infected animals in response to iBTK (ibrutinib) treatment. Our goal was to assess the effect of iBTK on TMEV induced disease pathology and disability.
Twenty six 8-11 week old mice were bilaterally, intra-cerebrally injected with TMEV and equally divided into iBTK (n=13) or vehicle control (n=13) treatment groups. Daily treatment with iBTK at 6 mg/kg started at 1 month post induction (mPI). Clinical disability score (CDS) on a 5 point scale, body weight and rotarod performance were recorded at 1 to 5 mPI. Half of the study animals were sacrificed at 3 mPI and their spinal cord tissue lesion load was analyzed with Iba1 microglia staining. TMEV infection was confirmed using ELISA on blood plasma. CD19 expressing B cell fraction of peripheral blood mono-nuclear cells was measured.
ELISA confirmed that all TMEV injected mice produced anti-TMEV antibodies. Furthermore, CD19 expressing B cell fraction was significantly reduced in iBTK treated mice (6.65±1.92%) relative to vehicle treated mice (12.51±2.34%) (p = 0.0428, T test). IBTK significantly improved longitudinal changes in CDS (p<0.001), body weights (p = 0.033) and rotarod latency measures (p=0.0477) in treated TMEV mice (repeated measures ANOVA). Additionally, Iba1 staining showed that TMEV animal spinal cord lesion area was significantly lower in white matter regions (p = 0.016, T test) and was trending lower in grey matter regions (p = 0.107, T test) in iBTK treated animals relative to vehicle treated mice.
BTK inhibition decreased B cell fraction and microglia activation in treated TMEV mice, resulting in lower lesion load of spinal cord tissue. Consequently, iBTK restricted TMEV disease induced clinical disability, body weight loss and motor dysfunction. To further characterize the impact of iBTK on MS disease pathology, future studies will assess neuro-degenerative immune cells and immune cell infiltration using neuroimaging.