Pulmonary macrophage transplantation therapy

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. This study reports the correction of pulmonary alveolar proteinosis (PAP) in Csf2rb –/– mice by a single transfer of either wild-type or gene-corrected macrophages directly to the lungs — the transplanted macrophages persisted for at least 1 year; this transplantation strategy obviated the need for myeloablation and immunosuppression and should be a feasible therapy for humans with hereditary PAP. Cell transplantation in lung disease Mutations in the receptor for granulocyte–macrophage colony-stimulating factor (GM-CSF) cause pulmonary alveolar proteinosis (PAP), a hereditary disease that results in respiratory failure due to an accumulation of surfactant. No pharmacological therapy exists for this disease, and surfactant must be removed by lung lavage. PAP can be cured in mouse models by bone marrow transplantation of gene-corrected haematopoietic stem cells, but this approach has not proved feasible in humans due to infection during the necessary myeloablation/immunosuppression. Bruce Trapnell and colleagues now report correction of PAP in mice after a single transfer of gene-corrected macrophages directly to the lungs. The gene corrected macrophages persisted for at least one year. Su