IMEX   05356
INSTITUTO DE MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
The Btk inhibitor ibrutinib impairs macrophage response to Mycobacterium tuberculosis and M1 polarization. Implications in long-term therapies with ibrutinib.
Autor/es:
COLADO A; ALMEJÚN, MB; PODAZA, E; RISNIK, D; GIORNADO, M; SASIAIN MC; GAMBERALE, R; BALBOA L; BORGE, M
Reunión:
Congreso; Reunión Anual de la Sociedad Argentina de Inmunología; 2015
Institución organizadora:
LASID SAI FAIC
Resumen:
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 (Mac). Besides, it is known that many drugs affecting immune cells are associated with higher risk of tuberculosis reactivation, worsening the underlying disease. Therefore, we asked if ibrutinib may affect Mac polarization impairing the response against Mycobacterium tuberculosis (Mtb).Macrophages were differentiated from healthy donor´s monocytes. GM-CSF plus IFN-g or M-CSF plus IL-4 or IL-10 were used to induce M1, M2a or M2c polarization respectively. Clinically relevant doses of ibrutinib were added to the cultures during polarization. HLA-DR, MR, CD86, CD16, CD163, CD14 and MerTK expression were assessed by flow cytometry. TNF-a was measured by ELISA after Mac stimulation with irradiated Mtb for 24 hours. We found that ibrutinib impairs M1, but not M2, polarization by downregulating CD86 and upregulating MR, CD16, CD163, CD14 expression (n=6 p˂0.05 control vs ibru), while HLA-DR and MerTK expression were not modified. Interestingly, we found that ibrutinib impairs TNF-a production by Mac stimulated with Mtb (n=10, p˂0.05).In conclusion we found that ibrutinib impairs M1 polarization and TNF-a production by Mac in response to Mtb. Our results suggest that Mtb response might be compromised in patients treated for long periods with ibrutinib.