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 r are lung disease characterized by excessive surfactant accumulation wi thin the alveolar space, remains obscure. Gene-targeted mice lacking t he hematopoietic growth factor granulocyte-macrophage colony-stimulati ng factor (GM-CSF) or the signal-transducing beta-common chain of the GM-CSF receptor have impaired surfactant clearance and pulmonary patho logy 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 mu g/kg/d was of normal magnitude. B y contrast, despite normal expression of GM-CSF receptor alpha- and be ta-common chains on peripheral blood myelomonocytic cells (n = 6) and normal binding affinity of bone marrow mononuclear cells for GM-CSF (n = 3), each of the 12 patients with acquired PAP treated displayed imp aired responses to GM-CSF; 5 mu g/kg/d produced only minor eosinophili a, and doses of 7.5 to 20 mu g/kg were required to induce greater than or equal to 1.5-fold neutrophil increments in the 3 patients who unde rwent dose-escalation. However, neutrophilic responses to 5 mu g/kg gr anulocyte colony-stimulating factor (G-CSF) were normal (n = 4), In vi tro, the proportion of hematopoietic progenitors responsive to GM-CSF (16.1% +/- 8.9%; P = .042) or interleukin-3 (IL-3: 19.3% +/- 7.7%; P = .063), both of which utilize the beta-common chain of the GM-CSF rece ptor complex, were reduced among patients with acquired PAP (n = 4) co mpared with normal bone marrow donor controls (47.2% +/- 25.9% and 40. 9% +/- 18.6%, respectively). In the one individual who had complete re solution of lung disease during the period of study, this was temporal ly associated with correction of this defective in vitro response to G M-CSF and IL-3 on serial assessment. These data establish that patient s with acquired PAP have an associated impaired responsiveness to GM-C SF that is potentially pathogenic in the development of their lung dis ease. Based on these observations, we propose a model of the pathogene sis of acquired PAP that suggests the disease arises as a consequence of an acquired clonal disorder within the hematopoietic progenitor cel l compartment. (C) 1998 by The American Society of Hematology.