Suzuki, TakujiArumugam, ParithaSakagami, TakuroLachmann, NicoChalk, ClaudiaSallese, AnthonyAbe, ShuichiTrapnell, ColeCarey, BrennaMoritz, ThomasMalik, PunamLutzko, CarolynWood, Robert E.Trapnell, Bruce C.2015-05-042014Suzuki, T., P. Arumugam, T. Sakagami, N. Lachmann, C. Chalk, A. Sallese, S. Abe, et al. 2014. “Pulmonary Macrophage Transplantation Therapy.” Nature 514 (7523): 450-454. doi:10.1038/nature13807. http://dx.doi.org/10.1038/nature13807.0028-0836http://nrs.harvard.edu/urn-3:HUL.InstRepos:15034855SUMMARY 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 independent of hematologic progenitors prompted us to consider organ-targeted, cell-specific therapy. Here, using GM-CSF receptor-β deficient (Csf2rb−/−) mice that develop a myeloid cell disorder identical to hereditary pulmonary alveolar proteinosis (hPAP) in children with CSF2RA/CSF2RB mutations, we show that pulmonary macrophage transplantation (PMT) of either wild-type or Csf2rb-gene-corrected macrophages without myeloablation was safe, well-tolerated, and that one administration corrected the lung disease, secondary systemic manifestations, normalized disease-related biomarkers, and prevented disease-specific mortality. PMT-derived alveolar macrophages persisted for at least one year as did therapeutic effects. Results 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.en-USGM-CSFM-CSFAlveolar MacrophageSurfactant HomeostasisMyeloid Cell DisorderGene TherapyGenetic DiseaseJournal Article2015-05-0410.1038/nature13807