RT Journal Article
SR Electronic
T1 Pulmonary transplantation of macrophage progenitors as effective and long-lasting therapy for hereditary pulmonary alveolar proteinosis
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP 250ra113
OP 250ra113
DO 10.1126/scitranslmed.3009750
VO 6
IS 250
A1 Happle, Christine
A1 Lachmann, Nico
A1 Škuljec, Jelena
A1 Wetzke, Martin
A1 Ackermann, Mania
A1 Brennig, Sebastian
A1 Mucci, Adele
A1 Jirmo, Adan Chari
A1 Groos, Stephanie
A1 Mirenska, Anja
A1 Hennig, Christina
A1 Rodt, Thomas
A1 Bankstahl, Jens P.
A1 Schwerk, Nicolaus
A1 Moritz, Thomas
A1 Hansen, Gesine
YR 2014
UL http://stm.sciencemag.org/content/6/250/250ra113.abstract
AB Hereditary pulmonary alveolar proteinosis (herPAP) is a rare lung disease caused by mutations in the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor genes, resulting in disturbed alveolar macrophage differentiation, massive alveolar proteinosis, and life-threatening respiratory insufficiency. So far, the only effective treatment for herPAP is repetitive whole-lung lavage, a merely symptomatic and highly invasive procedure. We introduce pulmonary transplantation of macrophage progenitors as effective and long-lasting therapy for herPAP. In a murine disease model, intrapulmonary transplanted macrophage progenitors displayed selective, long-term pulmonary engraftment and differentiation into functional alveolar macrophages. A single transplantation ameliorated the herPAP phenotype for at least 9 months, resulting in significantly reduced alveolar proteinosis, normalized lung densities in chest computed tomography, and improved lung function. A significant and sustained disease resolution was also observed in a second, humanized herPAP model after intrapulmonary transplantation of human macrophage progenitors. The therapeutic effect was mediated by long-lived, lung-resident macrophages, which displayed functional and phenotypical characteristics of primary human alveolar macrophages. Our findings present the concept of organotopic transplantation of macrophage progenitors as an effective and long-lasting therapy of herPAP and may also serve as a proof of principle for other diseases, expanding current stem cell–based strategies toward potent concepts using the transplantation of differentiated cells.