Modulation of granulocyte kinetics by GM-CSF/IFN-γ in a human LPS rechallenge model

• Published in: Journal of leukocyte biology Vol. 94; no. 3; pp. 513 - 520
• Main Authors: Kamp, Vera M., Leentjens, Jenneke, Pillay, Janesh, Langereis, Jeroen D., Kleijn, Stan, Kox, Matthijs, Netea, Mihai G., Pickkers, Peter, Koenderman, Leo
• Format: Journal Article
• Language: English
• Published: United States Society for Leukocyte Biology 01-09-2013
• Subjects: endotoxemia; endotoxin tolerance; eosinophil; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology; Granulocytes - drug effects; Granulocytes - immunology; Humans; Interferon-gamma - pharmacology; Interleukin-10 - biosynthesis; Interleukin-6 - biosynthesis; L-Selectin - analysis; Lipopolysaccharides - pharmacology; Male; myeloid‐derived suppressor cells; neutrophil; Tumor Necrosis Factor-alpha - biosynthesis; eosinophil; endotoxin tolerance; neutrophil; myeloid-derived suppressor cells; endotoxemia
• ISSN: 0741-5400; 1938-3673
• DOI: 10.1189/jlb.0213066

Immunotherapeutic agents for treatment of inflammatory diseases, GM‐CSF and IFNγ, dampen the systemic granulocytic response during repetitive human endotoxemia.
Inflammation in response to infection or trauma can lead to CARS, which is characterized by leukocyte dysfunction. In this study, we used a human model system for CARS to study the effect of GM‐CSF and IFN‐γ treatment on this immunoparalyzed state. Healthy human volunteers were treated with GM‐CSF (4 μg/kg), IFN‐γ (100 μg), or placebo in between two challenges with Escherichia coli LPS/endotoxin (2 ng/kg). Serial leukocyte blood counts were measured. Neutrophil subsets were discriminated using CD16 and CD62L expression. LPS rechallenge resulted in increased mobilization of mature neutrophils, whereas banded neutrophils decreased. GM‐CSF and IFN‐γ treatment did not restore these changes. GM‐CSF treatment did, however, increase the number of CD16bright/CD62Ldim neutrophils that were previously shown be able to suppress T cell proliferation. IFN‐γ treatment decreased neutrophilia seen after LPS rechallenge. Our study shows that LPS rechallenge was associated with changes in the distribution of neutrophil subsets, whereas no additional changes in kinetics of other granulocyte populations were observed. GM‐CSF and IFN‐γ treatment induced a shift in granulocyte composition toward an anti‐inflammatory direction by increasing CD16bright/CD62Ldim cells or decreasing neutrophil counts, respectively.