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Pulmonary transplantation of macrophage progenitors as effective and long-lasting therapy for hereditary pulmonary alveolar proteinosis.

Science translational medicine (2014-08-22)
Christine Happle, Nico Lachmann, Jelena Škuljec, Martin Wetzke, Mania Ackermann, Sebastian Brennig, Adele Mucci, Adan Chari Jirmo, Stephanie Groos, Anja Mirenska, Christina Hennig, Thomas Rodt, Jens P Bankstahl, Nicolaus Schwerk, Thomas Moritz, Gesine Hansen
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
D.E.R. 332, used as embedding medium
Sigma-Aldrich
2,6-Diisopropylphenol, 97%
Propofol, European Pharmacopoeia (EP) Reference Standard
Supelco
2,6-Diisopropylphenol, analytical standard
Propofol for peak identification, European Pharmacopoeia (EP) Reference Standard