Patient-derived granulocyte/macrophage colony-stimulating factor autoantibodies reproduce pulmonary alveolar proteinosis in nonhuman primates.
BACKGROUND
Granulocyte/macrophage colony-stimulating factor (GM-CSF) autoantibodies (GMAb) are strongly associated with idiopathic pulmonary alveolar proteinosis (PAP) and are believed to be important in its pathogenesis. However, levels of GMAb do not correlate with disease severity and GMAb are also present at low levels in healthy individuals.


OBJECTIVE
Our primary objective was to determine whether human GMAb would reproduce PAP in healthy primates. A secondary objective was to determine the concentration of GMAb resulting in loss of GM-CSF signaling in vivo (i.e., critical threshold).


METHODS
Nonhuman primates (Macaca fascicularis) were injected with highly purified, PAP patient-derived GMAb in dose-ranging (2.2-50 mg) single and multiple administration studies, and after blocking antihuman immunoglobulin immune responses, in chronic administration studies maintaining serum levels greater than 40 microg/ml for up to 11 months.


RESULTS
GMAb blocked GM-CSF signaling causing (1) a milky-appearing bronchoalveolar lavage fluid containing increased surfactant lipids and proteins; (2) enlarged, foamy, surfactant-filled alveolar macrophages with reduced PU.1 and PPARgamma mRNA, and reduced tumor necrosis factor-alpha secretion; (3) pulmonary leukocytosis; (4) increased serum surfactant protein-D; and (5) impaired neutrophil functions. GM-CSF signaling varied inversely with GMAb concentration below a critical threshold of 5 microg/ml, which was similar in lungs and blood and to the value observed in patients with PAP.


CONCLUSIONS
GMAb reproduced the molecular, cellular, and histopathologic features of PAP in healthy primates, demonstrating that GMAb directly cause PAP. These results have implications for therapy of PAP and help define the therapeutic window for potential use of GMAb to treat other disorders.
Sakagami
Takuro
T
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA.
Beck
David
D
Uchida
Kanji
K
Suzuki
Takuji
T
Carey
Brenna C
BC
Nakata
Koh
K
Keller
Gary
G
Wood
Robert E
RE
Wert
Susan E
SE
Ikegami
Machiko
M
Whitsett
Jeffrey A
JA
Luisetti
Maurizio
M
Davies
Stella
S
Krischer
Jeffrey P
JP
Brody
Alan
A
Ryckman
Fred
F
Trapnell
Bruce C
BC
D000818:Animals; D001323:Autoantibodies / Q000009:adverse effects*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology*; D006801:Humans; D008252:Macaca fascicularis; D016676:Macrophages, Alveolar / Q000000981:diagnostic imaging / Q000276:immunology*; D011649:Pulmonary Alveolar Proteinosis / Q000276:immunology* / Q000473:pathology; D014463:Ultrasonography
D001323:Autoantibodies; D016178:Granulocyte-Macrophage Colony-Stimulating Factor