Patient-derived Granulocyte/Macrophage Colony–Stimulating Factor Autoantibodies Reproduce Pulmonary Alveolar Proteinosis in Nonhuman Primates

• DOI: 10.1164/rccm.201001-0008oc
• Publication Date: 2010-03-12T03:25:28Z
• Authors: Takuro Sakagami; David Beck; Kanji Uchida; Takuji Suzuki; Brenna C. Carey; Koh Nakata; Gary Keller; Robert E. Wood; Susan E. Wert; Machiko Ikegami; Jeffrey A. Whitsett; Maurizio Luisetti; Stella Davies; Jeffrey P. Krischer; Alan Brody; Fred Ryckman; Bruce C. Trapnell
• Keywords: Pulmonary alveolar proteinosis; Alveolar macrophage

Granulocyte/macrophage colony-stimulating factor (GM-CSF) autoantibodies (GMAb) are strongly associated with idiopathic pulmonary alveolar proteinosis (PAP) and believed to be important in its pathogenesis. However, levels of GMAb do not correlate disease severity also present at low healthy individuals.Our primary objective was determine whether human would reproduce PAP primates. A secondary the concentration resulting loss GM-CSF signaling vivo (i.e., critical threshold).Nonhuman primates (Macaca fascicularis) were injected highly purified, patient-derived dose-ranging (2.2-50 mg) single multiple administration studies, after blocking antihuman immunoglobulin immune responses, chronic studies maintaining serum greater than 40 microg/ml for up 11 months.GMAb blocked causing (1) a milky-appearing bronchoalveolar lavage fluid containing increased surfactant lipids proteins; (2) enlarged, foamy, surfactant-filled macrophages reduced PU.1 PPARgamma mRNA, tumor necrosis factor-alpha secretion; (3) leukocytosis; (4) protein-D; (5) impaired neutrophil functions. varied inversely below threshold 5 microg/ml, which similar lungs blood value observed patients PAP.GMAb reproduced molecular, cellular, histopathologic features primates, demonstrating that directly cause PAP. These results have implications therapy help define therapeutic window potential use treat other disorders.