RAPID COMMUNICATION Attenuated Hematopoietic Response to Granulocyte-Macrophage Colony-Stimulating Factor in Patients With Acquired Pulmonary Alveolar Proteinosis

The pathogenesis of acquired pulmonary alveolar proteinosis (PAP), a rare lung disease characterized by excessive surfactant accumulation within the alveolar space, remains obscure. Gene-targeted mice lacking the hematopoietic growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF) or the signal-transducing b-common chain of the GM-CSF receptor have impaired surfactant clearance and pulmonary pathology resembling human PAP. We therefore investigated the hematopoietic effects of GM-CSF in patients with PAP. The hematologic response of 5 infants with congenital PAP to 5 mg/kg/d was of normal magnitude. By contrast, despite normal expression of GM-CSF receptor aand b-common chains on peripheral blood myelomonocytic cells (n 5 6) and normal binding affinity of bone marrow mononuclear cells for GM-CSF (n 5 3), each of the 12 patients with acquired PAP treated displayed impaired responses to GM-CSF; 5 mg/kg/d produced only minor eosinophilia, and doses of 7.5 to 20 mg/kg were required to induce H1.5-fold neutrophil increments in the 3 patients who underwent dose-escalation. However, neutrophilic responses to 5 mg/kg granulocyte colony-stimulating factor (G-CSF) were normal (n 5 4). In vitro, the proportion of hematopoietic progenitors responsive to GM-CSF (16.1% 6 8.9%; P 5 .042) or interleukin-3 (IL-3; 19.3% 6 7.7%; P 5 .063), both of which utilize the b-common chain of the GM-CSF receptor complex, were reduced among patients with acquired PAP (n 5 4) compared with normal bone marrow donor controls (47.2% 6 25.9% and 40.9% 6 18.6%, respectively). In the one individual who had complete resolution of lung disease during the period of study, this was temporally associated with correction of this defective in vitro response to GM-CSF and IL-3 on serial assessment. These data establish that patients with acquired PAP have an associated impaired responsiveness to GM-CSF that is potentially pathogenic in the development of their lung disease. Based on these observations, we propose a model of the pathogenesis of acquired PAP that suggests the disease arises as a consequence of an acquired clonal disorder within the hematopoietic progenitor cell compartment. r 1998 by The American Society of Hematology.