Inhibition of abl tyrosine kinase supports antimicrobial activity in human alveolar macrophages

Objective: Inhibition of abl tyrosine kinase by Gleevec® has revolutionized the therapy of chronic myeloic leukemia. The therapeutic manipulation of this ubiquitously expressed enzyme requires careful evaluation of potential side effects. This study was designed to investigate the functional implication of Gleevec® on the interaction of Mycobacterium tuberculosis (M.Tb) and its natural host cell, the alveolar macrophage.

Methods: Human alveolar macrophages were purified from bronchoalveolar lavage cells and infected with virulent M. Tb. Intracellular growth, phagosomal acidification and the expression of antimicrobial peptides was compared in the presence or absence of Gleevec.

Results: First we established by Western blot analysis that infection with M. Tb induces abl tyrosine kinase activity. Inhibition of this interaction by Gleevec triggered increased killing of intracellular M. Tb (56±14%) in six independent donors. Using a pH-dependent fluorochrome we demonstrate that increased antimicrobial activity is mediated by promotion of phagosomal acidification. As the ultimate effector mechanism we identify increased levels of the antimicrobial peptide cathelicidin (+39±15; n=4), which is cleaved from its inactive precursor to the bioactive form in the acidic environment.

Conclusion: Therapeutic inhibition of abl tyrosine kinase during leukemia treatment should not predispose to infections with intracellular pathogens and may even result in triggering antimicrobial effector mechanisms of innate immunity.

Heiko Bruns
geb. am 18.9.1979 auf Borkum

Wissenschaftliche Ausbildung:
2001–2006	Biologie Studium an der Universität Erlangen
2006	Diplomarbeit bei Prof. Dr. Stenger am Institut für Medizinische Mikrobiologie, Immunologie und Hygiene in Erlangen Titel: Mechanismen der erhöhten Tuberkulose-Inzidenz unter Therapie mit Tumor-Nekrose-Faktor Antikörpern
seit 1. 1. 2007	Doktorarbeit bei Prof. Dr. Stenger am Institut für Medizinische Mikrobiologie und Hygiene in Ulm Thema: Einfluss von Biologicals auf die Immunantwort bei der Tuberkulose

Publikationen:

1. Tan BH, Meinken C, Bastian M, Bruns H, Legaspi A, Ochoa MT, Krutzik SR, Bloom BR, Ganz T, Modlin RL, Stenger S. Macrophages acquire neutrophil granules for antimicrobial activity against intracellular pathogens. J. Immunol. 177, 1864–1871, 2006

2. Bastian M, Braun T, Bruns H, Röllinghoff M, Stenger S. Mycobacterial lipopeptides elicit CD4+ CTLs in Mycobacterium tuberculosis-infected humans. J. Immunol. 180, 3436–3446, 2008.

3. Wollin M, Abele S, Bruns H, Weyand M, Kalden JR, Ensminger SM, Spriewald BM. Inhibition of TNF-alpha reduces transplant arteriosclerosis in a murine aortic transplant model. Transplant Int. im Druck

Heiko Bruns

Institut für Medizinische Mikrobiologie und Hygiene

Universitätsklinikum Ulm

Albert-Einstein-Allee 11

89081 Ulm