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.
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This work was supported by grants from the NIH (R01 HL085453, R21 HL106134, R01HL118342, 8UL1TR000077-05, AR-47363, DK78392, DK90971), American Thoracic Society Foundation Unrestricted Research Grant, CCHMC Foundation Trustee Grant, Deutsche Forschungsgemeinschaft (DFG; Cluster of Excellence Rebirth; Exc 62/1), the Else Kröner-Fresenius Stiftung, the Eva-Luise Koehler Research Prize for Rare Diseases 2013, and by the Pulmonary Biology Division, CCHMC. Flow cytometric data were acquired within the Research Flow Cytometry Core in the Division of Rheumatology, CCHMC. We thank our hPAP patients and their family members in the United States and internationally for their collaboration; J. Whitsett (CCHMC) and F. McCormack (UCMC) for critical reading of the manuscript; J. Krischer (University of South Florida) and Y. Maeda (CCHMC) for helpful discussions; S. Wert for help with lung histology; and D. Black, K. Link and C. Fox (CCHMC), and S. Brennig and H. Kempf (Hannover Medical School) for their technical help.
The authors declare no competing financial interests.
Extended data figures and tables
a, Typical lung pathology showing surfactant-filled alveoli with well-preserved septa in a child homozygous for CSF2RBS271L mutations and identical pulmonary histopathology in a Csf2rb−/− mouse. PAS stain. Scale bar, 100 μm. b, Photographs of ‘milky’-appearing BAL from a 14-month-old Csf2rb−/− mouse and normal-appearing BAL from an age-matched WT mouse (representative of n = 6 mice per group). c, Increased BAL turbidity and SP-D concentration in 4-month-old Csf2rb−/− mice compared to age-matched WT mice. d, BAL fluid biomarkers of hPAP (GM-CSF, M-CSF and MCP-1) are increased in 4-month-old Csf2rb−/− mice compared to age-matched WT mice. e, Alveolar macrophage biomarkers (PU.1, Pparg, Abcg1 mRNA) are reduced in 4-month-old Csf2rb−/− compared to age-matched WT mice. f, Progressive increase in BAL turbidity in Csf2rb−/− mice but not age-matched WT mice (linear regression: Csf2rb−/−, slope = 0.1271 ± 0.16 (r2, 0.311); WT, slope = 0.031 ± 0.005). g, Progressive increase in BAL fluid GM-CSF level in Csf2rb−/− mice but not age-matched WT mice (linear regression: Csf2rb−/−, slope = 0.89 ± 0.016 (r2, 0.249); WT, slope = 0). h, GM-CSF bioactivity in BAL fluid from 10-month-old Csf2rb−/− or WT mice (or 1 ng ml−1 murine GM-CSF) measured in the presence of anti-GM-CSF antibody (GM-CSF Ab) or isotype control (Control Ab) using the GM-CSF-stimulated STAT5 phosphorylation index (STAT5-PI) assay. Data are mean ± s.e.m. of n = 7 mice per group (c–e), n = 4 (h) or symbols representing individual WT (n = 38) or Csf2rb−/− (n = 84) mice and regression fit ± 95% CI (f-g). *P < 0.05, **P < 0.01, ***P < 0.001. ns, not significant.
a, b, Photomicrographs of WT BMDMs before transplantation phase-contrast (a) or DiffQuick staining (b) (representative of n = 7 BMDM preparations). Scale bar, 20 μm. c, Flow cytometry evaluation of cell-surface phenotypic markers on WT BMDMs before PMT. d, Photographs of methylcellulose cultures of Lin– cells (5,000 per dish) from bone marrow (left) and BMDMs (50,000 per dish) prepared as described in the Methods (right) and typical colonies (below) (representative n = 3 per condition). e, Colony counts of BFU-E, CFU-GEMM and CFU-GM showing that BMDMs contained <0.005% CFU-GM and no BFU-E or CFU-GEMM progenitors, corresponding to 93 CFU-GM per dose of BMDMs administered (n = 3 determinations per condition). f, g, Evaluation of surfactant clearance capacity. Representative photomicrographs of BMDMs from WT (left) or Csf2rb−/− (right) were examined before (top) or immediately after incubation with surfactant for 24 h (middle), or after exposure, removal of extracellular surfactant and culture for 24 h in the absence of surfactant (lower) after oil-red-O staining (representative of n = 3 per condition). Scale bar, 20 μm. g, Measurement of surfactant clearance by BMDMs after exposure as just described (f) and quantified using a visual grading scale (the oil-red-O staining index) to measure the degree of staining. Bars represent the mean ± s.e.m. (n = 3 per condition) of oil-red-O staining score for 10 high-power fields for each group. ND, not detected; ns, not significant; ***P < 0.001.
Extended Data Figure 3 Efficacy of PMT in Csf2rb−/− mice and characterization of macrophages after PMT.
a, Detection of CD131 (top) or actin (bottom) in BAL cells by western blotting 1 year after PMT (each lane represents one mouse of 6 per group). b, Representative cytology of BAL obtained 1 year after PMT after staining with PAS or oil red O (ORO) (6 mice per group). Scale bar, 25 μm. Oil-red-O positive cells were seen rarely in WT mice and occasionally in PMT-treated Csf2rb−/− mice (insets). Cytological abnormalities in BAL from untreated Csf2rb−/− mice including large, ‘foamy’, PAS- and oil-red-O-stained alveolar macrophages and PAS-stained cellular debris, were corrected by PMT. c, Representative photomicrographs of PAS-stained whole-mount lung sections 1 year after PMT. Note that some residual disease remained at 1 year (original magnification, ×1). d, GFP+ cells in BAL cells from WT or Csf2rb−/− mice 2 months after PMT of Lys-MGFP BMDMs (representative of n = 3 (WT) or n = 6 (Csf2rb−/−) mice) (original magnfication, ×20). e, Macrophage replication after PMT. Csf2rb−/− mice received Lys-MGFP BMDMs by PMT and paraffin-embedded lung was immunostained for Ki67 1 month or 1 year later. Scale bar, 50 μm; inset, 10 μm. f, Ki67 staining of BAL cells from untreated WT mice (e). Inset shows positive (left) or negative (right) staining. Scale bar, 50 µm; inset 10 µm. Graph shows the per cent Ki67+ BAL cells in age-matched WT mice (n = 5). g, Representative immunofluorescence photomicrographs of frozen lung sections 1 year after PMT of Lys-MGFP into Csf2rb−/− mice identifying GFP+ cells (top), Ki67+ cells (middle) and GFP+Ki67+ (replicating, PMT-derived) cells (bottom) (representative of n = 3 mice). Scale bar, 20 μm; inset scale bar, 10 μm. Quantitative summary data are shown in Fig. 2c. h, Localization of macrophages within the lungs 1 year after PMT of Lys-MGFP BMDMs into Csf2rb−/− mice and visualization in frozen lung sections after CD68 immunostaining, DAPI counter staining, and fluorescence microscopy to detect CD68+GFP+ cells (that is, PMT-derived macrophages) or CD68+GFP– cells (that is, non-PMT-derived endogenous macrophages). Graph shows quantitative data for n = 6 mice. i, Localization of macrophages in these same mice (h) by detecting GFP by immunohistochemical staining of paraffin-embedded lung sections using light microscopy to eliminate potential interference from autofluorescence (representative of n = 6 mice). Quantitative summary data are shown in Fig. 3b.
Extended Data Figure 4 Tissue distribution and characterization of transplanted cells 1 year after PMT.
a–d, Two-month-old Csf2rb−/− mice (4 per group) received one PMT of Lys-MGFP BMDMs. Twelve months later, untreated, age-matched WT Lys-MGFP or Csf2rb−/− mice and PMT-treated Csf2rb−/− mice were evaluated using flow cytometry to detect GFP+ cells in the indicated organs. Representative data (a) and the percentage of GFP+ cells in the gated region are shown (b). Similar results were observed in Csf2rb−/− mice 2 months after PMT of Lys-MGFP BMDMs except the percentage of GFP+ BAL lung cells was not quantified (not shown). c, Detection of Lys-MGFP PMT cells by PCR. PCR of genomic DNA from BAL cells (Lung), white blood cells (Blood), bone marrow (BM) cells and splenocytes (Spleen) 1 month or 1 year after Lys-MGFP BMDM PMT was performed to detect EGFP and Lysozyme M gene. BAL cells (Lung) from WT and Lys-MGFP were shown as negative and positive control for EGFP. EGFP was only detected in lung. d, Vector copy number analysis after gene-corrected BMDM PMT. Quantitative PCR with vector-specific primers (R-U5) was performed using genomic DNA from BAL cells (Lung), white blood cells (Blood), bone marrow (BM) cells and splenocytes (Spleen) obtained 1 year after PMT of gene-corrected macrophages. Note that the viral vector was only detected in lung. e–h, CD45.2+ Csf2rb−/− mice received one PMT of CD45.1+ BMDMs from congenic WT mice (e) and 1 year later, untreated, age-matched WT (CD45.1+) or Csf2rb−/− (CD45.2+) mice and PMT-treated Csf2rb−/− mice were evaluated by flow cytometry to detect CD45.1+ cells in the indicated organs. Representative data (f) and the percentage of CD45.1+ cells in the gated regions are shown (g). Phenotypic characterization of PMT-derived (CD45.1+) cells (as shown in the gated region (f)). Results are similar to those for PMT of Lys-MGFP BMDMs (Fig. 3d). Numeric data are mean ± s.e.m. of n = 4 mice per group (b, d) or n = 5 mice per group (g). ND, not detected. *P < 0.05. ns, not significant.
Extended Data Figure 5 Global gene expression analysis of alveolar macrophages from age-matched WT, Csf2rb−/− and Csf2rb−/− mice 1 year after PMT of WT BMDMs.
a, Expression of Spi1 (PU.1) and Pparg (PPARγ) were confirmed by qRT–PCR using independent samples (6 mice per group). b, Venn diagrams showing numbers of genes whose expression was altered in alveolar macrophages from Csf2rb−/− compared to WT mice (WT→KO) or PMT-treated compared to untreated Csf2rb−/− mice (KO→KO+PMT). Only genes with statistically significant changes (false detection rate <10%) of at least twofold were marked as increased (up arrows) or decreased (down arrows). The numbers of genes for which expression was disrupted in Csf2rb−/− mice and normalized by PMT (or unchanged in both comparisons) is shown in the overlap regions. c, Gene ontology analysis identifying pathways disrupted in Csf2rb−/− mice and restored by PMT. Data show the coordinate increases (red) or decreases (blue) in expression of genes in all gene sets significant at or below a false detection rate of 10% calculated by the Gene Set Test with correction for multiple testing. d, Heat maps showing differentially expressed genes in multiple KEGG pathways including PPARγ-regulated genes, glycophospholipid metabolism, peroxisome function apoptosis, cell cycle control, and immune host defence. Genes with increased or decreased transcript levels are shown by red and blue colours, respectively. e, Confirmation by qRT–PCR for selected genes important in lipid metabolism, using independent samples. Data are mean ± s.e.m. (6 mice per group). *P < 0.05.
a, Macrophages derived from Csf2rb−/− LSK cells transduced with GM-R-LV or GFP-LV, or from non-transduced WT LSK cells (indicated) were examined by light microscopy after DiffQuick staining (top), or by immunofluorescence microscopy after staining with anti-CD131 (GM-CSF-R-β) and DAPI (upper middle), DAPI alone (lower middle), or anti-CD68 and DAPI (bottom). Images are representative of three experiments per condition. b, Evaluation of GM-CSF receptor signalling in the indicated cells (before PMT) by measurement of GM-CSF-stimulated STAT5 phosphorylation by flow cytometry. Representative of n = 3 experiments per condition. Quantitative summary data are shown in Fig. 5b. c, Western blotting to detect GM-CSF receptor-β (CD131) (top) or actin (bottom, as a loading control) in BAL cells from age-matched Csf2rb−/− mice 2 months after PMT as indicated (each lane represents one mouse of n = 10, 8, 10 per group, respectively). d, Appearance of BAL from age-matched Csf2rb−/− mice 2 months after PMT as indicated (representative of n = 10, 8, 10 per group, respectively). e, f, One year after PMT of GM-R-LV transduced Csf2rb−/− LSK cell-derived macrophages in Csf2rb−/− mice, GFP+ cells were identified (e) and evaluated for cell surface markers by flow cytometry (f) (representative of n = 7 mice).
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Suzuki, T., Arumugam, P., Sakagami, T. et al. Pulmonary macrophage transplantation therapy. Nature 514, 450–454 (2014). https://doi.org/10.1038/nature13807
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