title: Pulmonary macrophage transplantation therapy.
abstract: Bone-marrow transplantation is an effective cell therapy but requires myeloablation, which increases infection risk and mortality. Recent lineage-tracing studies documenting that resident macrophage populations self-maintain independently of haematological progenitors prompted us to consider organ-targeted, cell-specific therapy. Here, using granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor-β-deficient (Csf2rb(-/-)) mice that develop a myeloid cell disorder identical to hereditary pulmonary alveolar proteinosis (hPAP) in children with CSF2RA or CSF2RB mutations, we show that pulmonary macrophage transplantation (PMT) of either wild-type or Csf2rb-gene-corrected macrophages without myeloablation was safe and well-tolerated and that one administration corrected the lung disease, secondary systemic manifestations and normalized disease-related biomarkers, and prevented disease-specific mortality. PMT-derived alveolar macrophages persisted for at least one year as did therapeutic effects. Our findings identify mechanisms regulating alveolar macrophage population size in health and disease, indicate that GM-CSF is required for phenotypic determination of alveolar macrophages, and support translation of PMT as the first specific therapy for children with hPAP.
authors.affiliation: Division of Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Takuji
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Paritha
authors.initials: P
authors.lastname: Arumugam
authors.affiliation: Division of Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Takuro
authors.initials: T
authors.lastname: Sakagami
authors.affiliation: RG Reprograming and Gene Therapy, Institute of Experimental Hematology, Hannover Medical School, Carl Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Nico
authors.initials: N
authors.lastname: Lachmann
authors.affiliation: Division of Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Chalk
authors.affiliation: Division of Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Sallese
authors.affiliation: Division of Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Abe
authors.affiliation: 1] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA [2] Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Cole
authors.initials: C
authors.lastname: Trapnell
authors.affiliation: Division of Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Brenna
authors.initials: B
authors.lastname: Carey
authors.affiliation: RG Reprograming and Gene Therapy, Institute of Experimental Hematology, Hannover Medical School, Carl Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Moritz
authors.affiliation: Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Punam
authors.initials: P
authors.lastname: Malik
authors.affiliation: Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Lutzko
authors.affiliation: Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Wood
authors.affiliation: 1] Division of Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA [2] Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA [3] Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Trapnell
mesh_terms: D000818:Animals; D002469:Cell Separation; D017690:Cell Transplantation; D053648:Cytokine Receptor Common beta Subunit / Q000172:deficiency / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy; D008168:Lung / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000378:metabolism* / Q000637:transplantation*; D008297:Male; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011649:Pulmonary Alveolar Proteinosis / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D013997:Time Factors
chemical_list: D053648:Cytokine Receptor Common beta Subunit