Adjunctive GM-CSF therapy enhances host defense against systemicinfection in immunosuppressed mice.

Abstract

INTRODUCTION: is an emerging, multidrug-resistant fungal pathogen associated with high mortality in immunocompromised individuals. Resistance to current antifungal drugs emphasizes the need for new therapeutic approaches. We investigated granulocyte-macrophage colony-stimulating factor (GM-CSF) as a standalone immunotherapy and in combination with a sub-therapeutic dose of micafungin in an immunosuppressed mouse model of systemicinfection. METHODS: Immunosuppressed ICR CD-1 mice (4-6 weeks old) were infected withand treated daily via intraperitoneal injection with PBS (placebo), murine GM-CSF (0.2 or 2 μg), micafungin, or both. Treatments began 24 h post-infection and continued through day 4 (GM-CSF) or day 7 (micafungin). Survival, tissue fungal burden, histopathology, and immune cell frequencies in spleen and kidneys were assessed. GM-CSF effects on neutrophil and macrophage antifungal functions were evaluated inassays. RESULTS: GM-CSF monotherapy significantly improved survival (30-32% vs. 0% in controls), extended median survival time, and reduced fungal burden in the kidney, heart, and brain. Although the combination therapy yielded the highest survival rate, it did not differ significantly from GM-CSF alone. Histopathological examination confirmed decreased fungal load and tissue damage in GM-CSF-treated mice. Additionally, GM-CSF augmented macrophage and neutrophil populations in spleen and kidney, enhanced fungal uptake and killing via reactive oxygen species and neutrophil extracellular traps. DISCUSSION: GM-CSF augments antifungal immunity and represents a promising adjunctive immunotherapy against MDRinfection.