MICE LACKING GRANULOCYTE-COLONY-STIMULATING FACTOR HAVE CHRONIC NEUTROPENIA, GRANULOCYTE AND MACROPHAGE PROGENITOR-CELL DEFICIENCY, AND IMPAIRED NEUTROPHIL MOBILIZATION

Mice lacking granulocyte colony-stimulating factor (G-CSF) were genera ted by targeted disruption of the G-CSF gene in embryonal stem cells. G-CSF-deficient mice (genotype G-CSF-/-) are viable, fertile, and supe rficially healthy, but have a chronic neutropenia. Peripheral blood ne utrophil levels were 20% to 30% of wild-type mice (genotype G-CSF+/+) and mice heterozygous for the null mutation had intermediate neutrophi l levels, suggesting a gene-dosage effect. In the marrow of G-CSF-/- m ice, granulopoietic precursor cells were reduced by 50% and there were reduced levels of granulocyte, macrophage, and blast progenitor cells . Despite G-CSF deficiency, mature neutrophils were still present in t he blood and marrow, indicating that other factors can support neutrop hil production in vivo. G-CSF-/- mice had reduced numbers of neutrophi ls available for rapid mobilization into the circulation by a single d ose of G-CSF. G-CSF administration reversed the granulopoietic defect of G-CSF-/- mice. One day of G-CSF administration to G-CSF-/- mice ele vated circulating neutrophil levels to normal, and after 4 days of G-C SF administration, G-CSF+/+ and G-CSF-/- marrows were morphologically indistinguishable. G-CSF-/- mice had a markedly impaired ability to co ntrol infection with Listeria monocytogenes, with diminished neutrophi l and delayed monocyte increases in the blood and reduced infection-dr iven granulopoiesis. Collectively, these observations indicate that G- CSF is indispensible for maintaining the normal quantitative balance o f neutrophil production during ''steady-state'' granulopoiesis in vivo and also implicate G-CSF in ''emergency'' granulopoiesis during infec tions. (C) 1994 by The American Society of Hematology.