Granulocyte-macrophage colony-stimulating factor in the innate immune response to Pneumocystis carinii pneumonia in mice

Innate immunity plays an important role in pulmonary host defense against P neumocystis carinii, an important pathogen in individuals with impaired cel l-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 infec tion and were significantly greater than those in uninfected controls 3, 4, and 5 wk after inoculation. When GM-CSF gene-targeted mice (GM(-/-)) deple ted of CD4(+) cells were inoculated with P, carinii, the intensities of inf ection and inflammation were increased significantly compared with those in CD4-depleted mild-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 inflammat ion 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 r esponse was preserved in the GM(-/-) mice. However, alveolar macrophages (A M) from GM(-/-) mice demonstrated impaired phagocytosis of purified murine P, carinii organisms in vitro compared with AM from wild-type mice. Similar ly, AM production of TNF-alpha in response to P, carinii in vitro was total ly absent in AM from GM(-/-) mice,while GM-CSF-replete mice produced abunda nt TNF in this setting. Thus, GM-CSF plays a critical role in the inflammat ory response to P, carinii in the setting of impaired cell-mediated immunit y through effects on AM activation.