Attenuated hematopoietic response to granulocyte-macrophage colony-stimulating factor in patients with acquired pulmonary alveolar proteinosis

Seymour, JF; Begley, CG; Dirksen, U; Presneill, JJ; Nicola, NA; Moore, PE; Schoch, OD; van Asperen, P; Roth, B; Burdach, S; Dunn, AR

Author(s): Seymour, JF; Begley, CG; Dirksen, U; Presneill, JJ; Nicola, NA; Moore, PE; Schoch, OD; van Asperen, P; Roth, B; Burdach, S; Dunn, AR;
Details: Publication Year 1998-10-15,Volume 92,Issue #8,Page 2657-2667
Journal Title: BLOOD
Publication Type: Journal Article
Abstract: 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 beta-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 mu g/kg/d was of normal magnitude. By contrast, despite normal expression of GM-CSF receptor alpha- and beta-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 impaired responses to GM-CSF; 5 mu g/kg/d produced only minor eosinophilia, 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 underwent dose-escalation. However, neutrophilic responses to 5 mu g/kg granulocyte colony-stimulating factor (G-CSF) were normal (n = 4), In vitro, 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 receptor complex, were reduced among patients with acquired PAP (n = 4) compared with normal bone marrow donor controls (47.2% +/- 25.9% and 40.9% +/- 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. (C) 1998 by The American Society of Hematology.
Publisher: W B SAUNDERS CO
Keywords: RECEPTOR-DEFICIENT MICE; COMMON BETA-CHAIN; FACTOR GM-CSF; ADVANCED MALIGNANCY; PROGENITOR CELLS; GENE-EXPRESSION; STEM-CELLS; IN-VITRO; PHASE-I; CANCER
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Creation Date: 1998-10-15 12:00:00