The BTK inhibitor ibrutinib impairs the innate immune response against Mycobacterium tuberculosis mediated by macrophages and γδ T cell

COLADO, ANA; PODAZA, ENRIQUE; MARIN FRANCO, JOSE LUIS; KVIATCOVSKY, DENISE; JANCIC, CAROLINA; ELÍAS, ESTEBAN ENRIQUE; GENOULA, MELANIE; GAMBERALE, ROMINA; MARIDONNEAU-PARINI, ISABELLE; RISNIK, DENISE; SASIAIN, MARIA DEL CARMEN; COUGOULE, CÉLINE; BORGE, MERCEDES; GIORDANO, MIRTA; BALBOA, LUCIANA

Buenos Aires

Congreso; Reunión conjunta de sociedades de biociencia; 2017

The Bruton?s Tyrosine Kinase (Btk) inhibitor, ibrutinib(ibru), was recently approved for the treatment of ChronicLymphocytic Leukemia (CLL) patients. Previously wefound that ibru affected macrophage polarization andTNF-α secretion in response to M. tuberculosis (Mtb).Considering that ibru is being introduced in countrieswith high incidence rates of tuberculosis (TB), such asArgentina, we aimed to extend the study of the effect ofibru on the immune response to Mtb mediated by macrophagesand γδ T cells, which are central players in TBinnate immunity.Macrophages were differentiated by culturing humanmonocytes with M-CSF. TNF-α, IL-8 and IL-10 secretionwere measured by ELISA after macrophage stimulationwith irradiated Mtb, Pam3CSK4 or LPS for 24h.Phospho-p65 of NFkB was evaluated by Western blot.Phagocytosis of Mtb-FITC by macrophages was evaluatedby flow cytometry. Bacillary loads were determinedby colony-forming units assay. Human γδ T cells werepurified by using MicroBead isolation kit and after 24hof Mtb stimulation, IFN-γ was evaluated by ELISA andCD69 expression by flow cytometry. Statistical significancewas determined using the Friedman test and theDunn?s post-test.We found that ibru significantly reduced TNF-α, IL-10and IL-8 secretion (n=10, p˂0.05) and diminished phospho-p65 (n=5, p˂0.05) in response to Mtb. Moreover, ibruimpaired TNF-α secretion by macrophages in responseto LPS and Pam3CSK4 (n=10, p˂0.05). Then, we foundthat ibru significantly enhanced Mtb phagocytosis (n=14,p˂0.05) and preliminary results showed a slight increasein the bacillary loads obtained from ibru-treated macrophages.CD69 expression and IFN-γ secretion was impairedin ibru-treated γδ T cells in response to Mtb (n=8,p˂0.05).Our results suggest that the innate-immune responseto Mtb might be compromised in ibru-treated patients.Thus, increased awareness should be taken during ibrutreatment especially in countries with high incidencerates of TB.