Pulmonary macrophage transplantation therapy.
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
|