Asthma is a complex airways disease with a wide spectrum which ranges from eosinophilic (Th2 driven) to mixed granulocytic (Th2/Th17 driven) phenotypes. Mixed granulocytic
asthma is a cause of concern as
corticosteroids often fail to control this phenotype. Different
kinases such as Brutons's
tyrosine kinase (BTK) and
IL-2 inducible T cell kinase (ITK) play a pivotal role in shaping allergic airway
inflammation.
Ibrutinib is primarily a BTK inhibitor, however it is reported to be an ITK inhibitor as well. In this study, we sought to determine the effect of
Ibrutinib on Th1, Th17 and Th2 immune responses in a cockroach
allergen extract (CE)-induced mixed granulocytic (eosinophilic and neutrophilic) mouse model in preventative mode.
Ibrutinib attenuated neutrophilic
inflammation at a much lower doses (25-75 μg/mouse) in CE-induced mixed granulocytic
asthma whereas Th2/Th17 immune responses remained unaffected at these doses. However, at a much higher dose, i.e. 250 μg/mouse,
Ibrutinib remarkably suppressed both Th17/Th2 and lymphocytic/neutrophilic/eosinophilic airway
inflammation. At molecular level,
Ibrutinib suppressed phosphorylation of BTK in neutrophils at lower doses and ITK in CD4 + T cells at higher doses in CE-treated mice. Further, effects of
Ibrutinib were compared with
dexamethasone on CE-induced mixed granulocytic
asthma in therapeutic mode.
Ibrutinib was able to control granulocytic
inflammation along with Th2/Th17 immune response in therapeutic mode whereas
dexamethasone limited only Th2/eosinophilic
inflammation. Thus,
Ibrutinib has the potential to suppress both Th17/Th2 and neutrophilic/eosinophilic
inflammation during mixed granulocytic
asthma and therefore may be pursued as alternative therapeutic option in difficult-to-treat
asthma which is resistant to
corticosteroids.