Pulmonary macrophage transplantation therapy.

Nature
Authors
Keywords
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.

Year of Publication
2014
Journal
Nature
Volume
514
Issue
7523
Pages
450-4
Date Published
2014 Oct 23
ISSN
1476-4687
URL
DOI
10.1038/nature13807
PubMed ID
25274301
PubMed Central ID
PMC4236859
Links
Grant list
R01 HL069549 / HL / NHLBI NIH HHS / United States
8UL1TR000077-05 / TR / NCATS NIH HHS / United States
R01HL118342 / HL / NHLBI NIH HHS / United States
AR-47363 / AR / NIAMS NIH HHS / United States
R01 HL085453 / HL / NHLBI NIH HHS / United States
P30 DK078392 / DK / NIDDK NIH HHS / United States
R01 HL118342 / HL / NHLBI NIH HHS / United States
U54 HL127672 / HL / NHLBI NIH HHS / United States
DK90971 / DK / NIDDK NIH HHS / United States
R01HL085453 / HL / NHLBI NIH HHS / United States
P30 DK090971 / DK / NIDDK NIH HHS / United States
R21 HL106134 / HL / NHLBI NIH HHS / United States
UL1 TR000077 / TR / NCATS NIH HHS / United States
DK78392 / DK / NIDDK NIH HHS / United States
P30 AR047363 / AR / NIAMS NIH HHS / United States