The Btk inhibitor ibrutinib impairs macrophage response to Mycobacterium tuberculosis and M1 polarization. Implications in long-term therapies with ibrutinib.

COLADO ANA; ALMEJÚN MARÍA BELÉN; PODAZA ENRIQUE; RISNIK DENISE; GIORDANO MIRTA; SASIAIN MARÍA DEL CARMEN; GAMBERALE ROMINA; BALBOA LUCIANA; BORGE MERCEDES

Buenos Aires

Congreso; I Meeting LASID, FAIC, SAI 2015; 2015

Ibrutinib is an oral irreversible inhibitor of the Bruton Tyrosine Kinase (Btk) which has shown excellent response in patients with B cell malignancies. Ibrutinib is given once daily with no endpoint established yet, which means that patients receive this drug for long periods. We and others have reported that ibrutinb has effects on other cells besides malignant B cells such as macrophages. Given that macrophages, particularly M1, are important in the immune response to mycobacterium tuberculosis (Mtb), we asked if ibrutinib i) affects macrophage polarization and ii) impairs TNFα production by Mtb stimulated-macrophages.Macrophages were differentiated from healthy donor´s monocytes. GM-CSF plus IFNɣ or M-CSF plus IL4 and IL-10 were used to induce M1 or M2 polarization respectively. Clinically relevant doses of ibrutinib were added to the cultures for the last two days of polarization. HLA-DR, MR, CD86, CD16, CD163, CD14 and MerTK expression were assessed by flow cytometry. TNFα was measured by ELISA after macrophage stimulation with irradiated Mtb for 24 hours. We found that ibrutinib affects M1, but not M2, polarization by downregulating CD86 and upregulating MR, CD16, CD163, CD14 expression on M1 polarized macrophages (n=6 p˂0.05 control vs ibru), HLA-DR and MerTK expression were not modify. Interestingly, we found that ibrutinib impairs TNFα production by macrophages stimulated with Mtb (n=10, p˂0.05).In conclusion we found that ibrutinib impairs M1 polarization and TNFα production by macrophages in response to Mtb. Our results suggest that Mtb response might be compromised in patients treated for long periods with ibrutinib.