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Blood, Vol. 92 No. 8 (October 15), 1998:
pp. 2657-2667
RAPID COMMUNICATION
Attenuated Hematopoietic Response to Granulocyte-Macrophage
Colony-Stimulating Factor in Patients With Acquired Pulmonary
Alveolar Proteinosis
John F. Seymour,
C. Glenn Begley,
Uta Dirksen,
Jeffrey J. Presneill,
Nicos A. Nicola,
Paul E. Moore,
Otto D. Schoch,
Peter vanAsperen,
Bernhard Roth,
Stefan Burdach, and
Ashley R. Dunn
From the Ludwig Institute for Cancer Research, Parkville, Australia;
the Rotary Bone Marrow Research Laboratories, Parkville, Australia; the
Department of Pediatric Hematology/Oncology, Heinrich-Heine University
Medical Center, Düsseldorf, Germany; the Department of Clinical
Haematology and Medical Oncology, and the Intensive Care Unit, Royal
Melbourne Hospital, Parkville, Australia; the Walter and Eliza Hall
Institute of Medical Research, Parkville, Australia; the Children's
Hospital, Division of Respiratory Diseases, Boston, MA; the Pulmonary
Division, University Hospital, Zurich, Switzerland; the Royal Alexandra
Hospital for Children, Westmead, Australia; and the Department of
Pediatrics, University of Cologne, Cologne, Germany.
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  -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 µg/kg/d was of normal
magnitude. By contrast, despite normal expression of GM-CSF receptor
 - and -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 µg/kg/d produced only minor
eosinophilia, and doses of 7.5 to 20 µg/kg were required to induce
 1.5-fold neutrophil increments in the 3 patients who underwent
dose-escalation. However, neutrophilic responses to 5 µg/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 -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.
© 1998 by The American Society of Hematology.
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