Primary pulmonary alveolar proteinosis (PAP) is characterized by progressive accumulation of surfactant in the lungs resulting in respiratory failure as well as increased pulmonary and systemic infections that account for 18% of attributable mortality. Abrogation of GM-CSF signaling appears to be central to disease pathogenesis because GM-CSF knockout (GM-/-) mice develop PAP and have increased mortality from infection and because PAP in humans is associated with high levels of neutralizing anti-GM-CSF antibodies. We reported that GM-CSF is required to stimulate the terminal differentiation of alveolar macrophages (AMs) in mice and likely also in humans, and does so primarily via the hematopoietic transcription factor, PU.1. Neutrophil and monocyte counts are normal in PAP patients and GM-/- mice, suggesting GM-CSF has a critical role in the lung but not in hematopoiesis. Our Preliminary Data now show that low levels of anti-GM-CSF antibodies are present in disease-free, healthy individuals, and correlate inversely with neutrophil function;and that neutrophils are functionally impaired in both GMA/A mice and PAP patients. This proposal seeks to test the following general hypothesis: GM-CSF has a critical systemic role in innate immunity, stimulating mechanisms in myeloid cells determining basal levels of antimicrobial and other functions. Specifically, we hypothesize that (1) high levels of anti-GM-CSF antibodies are the cause of the clinical manifestations in PAP and not an epiphenomenon or a consequence of intercurrent microbial infection;and (2) low levels of anti-GM-CSF antibodies may play an important physiological role by binding and inactivating circulating GM-CSF, thereby modulating the basal immune responsiveness of myeloid cells.
In Aim 1, we will determine the mechanism(s) by which anti-GM-CSF antibodies regulate functions in myeloid cells, including AMs, monocytes and neutrophils.
In Aim 2, PAP will be recapitulated in healthy subjects by transfer of anti-GM-CSF antibodies from PAP patients into non-human primates, satisfying Koch's 2nd &3rd postulates.
In Aim 3, we will utilize a novel immune model of PAP in mice to determine the critical threshold level of anti-GM-CSF antibodies that abrogate GM-CSF bioactivity in vivo and determine the kinetics and pharmacodynamics of myeloid cell dysfunction and onset and resolution of PAP. Expected results will establish that anti-GM-CSF antibodies cause the clinical manifestations in PAP patients, and will determine underlying mechanisms of myeloid cell dysfunction. Results have biological implications for the role of GM-CSF in mucosal barrier function beyond PAP in both health and disease. Clinical implications exist for PAP therapies, and also for anti-GM-CSF antibody-based therapies to treat serious inflammatory disorders, an approach for which significant commercial interest and development have now emerged.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL085453-03
Application #
7581037
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Reynolds, Herbert Y
Project Start
2007-04-01
Project End
2011-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
3
Fiscal Year
2009
Total Cost
$375,000
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
McCarthy, Cormac; Avetisyan, Ruzan; Carey, Brenna C et al. (2018) Prevalence and healthcare burden of pulmonary alveolar proteinosis. Orphanet J Rare Dis 13:129
Hetzel, Miriam; Suzuki, Takuji; Hashtchin, Anna Rafiei et al. (2017) Function and Safety of Lentivirus-Mediated Gene Transfer for CSF2RA-Deficiency. Hum Gene Ther Methods 28:318-329
Kugathasan, Subra; Denson, Lee A; Walters, Thomas D et al. (2017) Prediction of complicated disease course for children newly diagnosed with Crohn's disease: a multicentre inception cohort study. Lancet 389:1710-1718
Sallese, Anthony; Suzuki, Takuji; McCarthy, Cormac et al. (2017) Targeting cholesterol homeostasis in lung diseases. Sci Rep 7:10211
Mucci, Adele; Kunkiel, Jessica; Suzuki, Takuji et al. (2016) Murine iPSC-Derived Macrophages as a Tool for Disease Modeling of Hereditary Pulmonary Alveolar Proteinosis due to Csf2rb Deficiency. Stem Cell Reports 7:292-305
Suzuki, Takuji; Trapnell, Bruce C (2016) Pulmonary Alveolar Proteinosis Syndrome. Clin Chest Med 37:431-40
Campo, Ilaria; Luisetti, Maurizio; Griese, Matthias et al. (2016) Whole lung lavage therapy for pulmonary alveolar proteinosis: a global survey of current practices and procedures. Orphanet J Rare Dis 11:115
Schnepp, Bruce C; Chulay, Jeffrey D; Ye, Guo-Jie et al. (2016) Recombinant Adeno-Associated Virus Vector Genomes Take the Form of Long-Lived, Transcriptionally Competent Episomes in Human Muscle. Hum Gene Ther 27:32-42
Campo, Ilaria; Luisetti, Maurizio; Griese, Matthias et al. (2016) A Global Survey on Whole Lung Lavage in Pulmonary Alveolar Proteinosis. Chest 150:251-3
Acciani, T H; Suzuki, T; Trapnell, B C et al. (2016) Epidermal growth factor receptor signalling regulates granulocyte-macrophage colony-stimulating factor production by airway epithelial cells and established allergic airway disease. Clin Exp Allergy 46:317-28

Showing the most recent 10 out of 31 publications