title: Pulmonary transplantation of macrophage progenitors as effective and long-lasting therapy for hereditary pulmonary alveolar proteinosis.
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.
authors.affiliation: Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, 30625 Hannover, Germany. Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), 30625 Hannover, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Happle
authors.affiliation: Reprogramming and Gene Therapy Group, REBIRTH Cluster-of Excellence, Hannover Medical School, 30625 Hannover, Germany. Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Nico
authors.initials: N
authors.lastname: Lachmann
authors.affiliation: Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Jelena
authors.initials: J
authors.lastname: Škuljec
authors.affiliation: Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Wetzke
authors.affiliation: Reprogramming and Gene Therapy Group, REBIRTH Cluster-of Excellence, Hannover Medical School, 30625 Hannover, Germany. Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Mania
authors.initials: M
authors.lastname: Ackermann
authors.affiliation: Reprogramming and Gene Therapy Group, REBIRTH Cluster-of Excellence, Hannover Medical School, 30625 Hannover, Germany. Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brennig
authors.affiliation: Reprogramming and Gene Therapy Group, REBIRTH Cluster-of Excellence, Hannover Medical School, 30625 Hannover, Germany. Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Adele
authors.initials: A
authors.lastname: Mucci
authors.affiliation: Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, 30625 Hannover, Germany. Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), 30625 Hannover, Germany.
authors.forename: Adan Chari
authors.initials: AC
authors.lastname: Jirmo
authors.affiliation: Institute of Cell Biology in the Center of Anatomy, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Groos
authors.affiliation: Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Mirenska
authors.affiliation: Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, 30625 Hannover, Germany. Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), 30625 Hannover, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Hennig
authors.affiliation: Department of Diagnostic and Interventional Radiology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rodt
authors.affiliation: Institute for Preclinical Molecular Imaging, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Jens P
authors.initials: JP
authors.lastname: Bankstahl
authors.affiliation: Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, 30625 Hannover, Germany. Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), 30625 Hannover, Germany.
authors.forename: Nicolaus
authors.initials: N
authors.lastname: Schwerk
authors.affiliation: Reprogramming and Gene Therapy Group, REBIRTH Cluster-of Excellence, Hannover Medical School, 30625 Hannover, Germany. Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Moritz
authors.affiliation: Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, 30625 Hannover, Germany. Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), 30625 Hannover, Germany. hansen.gesine@mh-hannover.de.
authors.forename: Gesine
authors.initials: G
authors.lastname: Hansen
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002675:Child, Preschool; D053648:Cytokine Receptor Common beta Subunit / Q000172:deficiency / Q000378:metabolism; D006801:Humans; D016040:Lung Transplantation; D008264:Macrophages / Q000637:transplantation*; D051379:Mice; D010641:Phenotype; D011649:Pulmonary Alveolar Proteinosis / Q000473:pathology / Q000628:therapy*; D033581:Stem Cell Transplantation; D013997:Time Factors
chemical_list: D053648:Cytokine Receptor Common beta Subunit