Pulmonary macrophage transplantation therapy

Takuji Suzuki (), Paritha Arumugam, Takuro Sakagami, Nico Lachmann, Claudia Chalk, Anthony Sallese, Shuichi Abe, Cole Trapnell, Brenna Carey, Thomas Moritz, Punam Malik, Carolyn Lutzko, Robert E. Wood and Bruce C. Trapnell ()
Additional contact information
Takuji Suzuki: Perinatal Institute, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA
Paritha Arumugam: Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA
Takuro Sakagami: Perinatal Institute, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA
Nico Lachmann: RG Reprograming and Gene Therapy, Institute of Experimental Hematology, Hannover Medical School, Carl Neuberg-Str. 1, 30625 Hannover, Germany
Claudia Chalk: Perinatal Institute, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA
Anthony Sallese: Perinatal Institute, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA
Shuichi Abe: Perinatal Institute, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA
Cole Trapnell: Harvard University
Brenna Carey: Perinatal Institute, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA
Thomas Moritz: RG Reprograming and Gene Therapy, Institute of Experimental Hematology, Hannover Medical School, Carl Neuberg-Str. 1, 30625 Hannover, Germany
Punam Malik: Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA
Carolyn Lutzko: Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA
Robert E. Wood: Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA
Bruce C. Trapnell: Perinatal Institute, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA

Nature, 2014, vol. 514, issue 7523, 450-454

Abstract: 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.

Date: 2014
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DOI: 10.1038/nature13807

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