Effects of IL-6 on the Efficacy of Liposomal Amphotericin B Alone or with Caspofungin for Treatment of Murine Pulmonary Aspergillus fumigatus Infection

J. Olson, D. Constable, T. Chang, J. Adler-Moore

Author address: 

Cal Poly Pomona, POMONA, USA

Abstract: 

Objectives: Cytokines of the innate immune response play a critical role in controlling pulmonary aspergillosis and this response can be modulated by antifungal drugs. The present study was done to examine the immune effects of combining liposomal amphotericin B (AmBisome, AmBi) with caspofungin (Cancidas,CS) or IL-6 for the treatment of Aspergillus fumigatus murine pulmonary infection. Methods: Swiss Webster (SW, Study 1) or DBA/2 (DB, Study 2) mice were immunosuppressed d-3, d0, d+2 with 6mg/kg (Study 1) or 2mg/kg triamcinolone acetonide (Study 2) and challenged intranasally with 5.8 X 10ex7 (SW) or 7.0 X 10ex6 (DB) A. fumigatus conidia/mouse. IV dosing post-challenge was initiated at 2h for SW and at 24h for DB: Study 1 (treatments on d0-d5), 5% dextrose (D5W), 5mg/kg AmBi, 5 mg/kg CS, 5mg/kg AmBi + 5mg/kg CS; Study 2 (treatments on d1-d3), D5W, 10mg/kg AmBi, 0.2μg IL-6 or 10mg/kg AmBi + 0.2μg IL-6. In both studies, mice (n=7/group) were monitored for morbidity for 14 days. In Study 1, blood was collected (n=5/group) 24h after the last treatment for cytokine analysis including γ IFN, IL1α , IL4, IL6, IL10, IL12, IL17, MIP1α and TNFα . Lung tissue (n=7/group) was collected for determination of Log10 CFU/g(CFU) 24h after 6 treatments (Study 1) or 2 treatments (Study 2). Results: In Study 1, IL-6 and γ IFN mean levels were significantly lower (P8804; 0.05) for AmBi (12ng/mL IL6; 52ng/mL γ IFN; 100% survival) or AmBi + CS (11ng/mL IL6; 28 ng/mL γ IFN; 100% survival) vs CS (70ng/mL IL6; 102 ng/mL γ IFN; 0% survival). IL-6 and γ IFN levels for AmBi (100% survival) and D5W (58% survival) were similar. There was also significantly lower lung fungal burden for AmBi (2.1CFU) or AmBi + CS (2.6 CFU) vs CS (4.7 CFU) or D5W (4.5 CFU) (P8804; 0.01). In Study 2, survival was better for AmBi (72%) vs D5W (0%) (P=0.002), IL-6 treatment (14%) (P=0.02) or IL-6 + AmBi (43%); there was also significantly lower lung fungal burden (P=0.0006) for AmBi (4.1 CFU) vs IL-6 treatment (7.1 CFU), AmBi + IL-6 (6.9 CFU) or D5W (7.3 CFU). Conclusion: Compared to CS, AmBi generated significantly lower proinflammatory IL-6 and γ IFN levels and AmBi was more effective than CS for treating steroid immunosuppressed A. fumigatus murine pulmonary aspergillosis. The efficacy of AmBi was significantly decreased by the addition of exogenous IL-6.
2009

abstract No: 

P323

Full conference title: 

4th Trends in Medical Mycology
    • TIMM 4th (2012)