Takuro Sakagami1, David Beck1,2, Kanji Uchida1, Takuji Suzuki1, Brenna C. Carey1, Koh Nakata3, Gary Keller4, Robert E. Wood5, Susan E. Wert1, Machiko Ikegami1, Jeffrey A. Whitsett1, Maurizio Luisetti6, Stella Davies7, Jeffrey P. Krischer8, Alan Brody9, Fred Ryckman10 and Bruce C. Trapnell1,2,5. American Journal of Respiratory and Critical Care Medicine Vol 182. pp. 49-61, (2010)
Rationale: 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.
Objectives: 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 µg/ml for up to 11 months.
Measurements and Main 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 PPAR mRNA, and reduced tumor necrosis factor- 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 µg/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.
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