Pulmonary macrophage transplantation therapy

Nature. 2014 Oct 23;514(7523):450-4. doi: 10.1038/nature13807. Epub 2014 Oct 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Separation
  • Cell Transplantation*
  • Cytokine Receptor Common beta Subunit / deficiency
  • Cytokine Receptor Common beta Subunit / genetics*
  • Female
  • Genetic Therapy*
  • Lung / cytology*
  • Lung / metabolism
  • Lung / pathology
  • Macrophages, Alveolar / metabolism*
  • Macrophages, Alveolar / transplantation*
  • Male
  • Mice
  • Oligonucleotide Array Sequence Analysis
  • Phenotype
  • Pulmonary Alveolar Proteinosis / genetics
  • Pulmonary Alveolar Proteinosis / pathology
  • Pulmonary Alveolar Proteinosis / therapy*
  • Time Factors

Substances

  • Cytokine Receptor Common beta Subunit

Associated data

  • GEO/GSE60528