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*Pneumocystis Infections
The Journal of Immunology, 2000, 164: 2602-2609.
Copyright © 2000 by The American Association of Immunologists

Granulocyte-Macrophage Colony-Stimulating Factor in the Innate Immune Response to Pneumocystis carinii Pneumonia in Mice1

Robert Paine, III2,*,{dagger}, Angela M. Preston*, Steven Wilcoxen*, Hong Jin*, Brian B. Siu*, Susan B. Morris*, Jacquelyn A. Reed{ddagger}, Gary Ross{ddagger}, Jeffrey A. Whitsett{ddagger} and James M. Beck*,{dagger}

* Division of Pulmonary and Critical Care Medicine, University of Michigan, and {dagger} Department of Veterans Affairs Medical Center, Ann Arbor, MI 48105; and {ddagger} Division of Pulmonary Biology, Children’s Hospital, Cincinnati, OH 45229

Innate immunity plays an important role in pulmonary host defense against Pneumocystis carinii, an important pathogen in individuals with impaired cell-mediated immunity. We investigated the role of GM-CSF in host defense in a model of P. carinii pneumonia induced by intratracheal inoculation of CD4-depleted mice. Lung GM-CSF levels increased progressively during the infection and were significantly greater than those in uninfected controls 3, 4, and 5 wk after inoculation. When GM-CSF gene-targeted mice (GM-/-) depleted of CD4+ cells were inoculated with P. carinii, the intensities of infection and inflammation were increased significantly compared with those in CD4-depleted wild-type mice. In contrast, transgenic expression of GM-CSF directed solely in the lungs of GM-/- mice (using the surfactant protein C promoter) dramatically decreased the intensity of infection and inflammation 4 wk after inoculation. The concentrations of surfactant proteins A and D were greater in both uninfected and infected GM-/- mice compared with those in wild-type controls, suggesting that this component of the innate response was preserved in the GM-/- mice. However, alveolar macrophages (AM) from GM-/- mice demonstrated impaired phagocytosis of purified murine P. carinii organisms in vitro compared with AM from wild-type mice. Similarly, AM production of TNF-{alpha} in response to P. carinii in vitro was totally absent in AM from GM-/- mice, while GM-CSF-replete mice produced abundant TNF in this setting. Thus, GM-CSF plays a critical role in the inflammatory response to P. carinii in the setting of impaired cell-mediated immunity through effects on AM activation.




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