Combined administration of anti‐ IL IL ‐13 and anti‐ IL IL ‐17A at individually sub‐therapeutic doses limits asthma‐like symptoms in a mouse model of Th2/Th17 high asthma

摘要

Summary Background Recent studies have demonstrated that Th2 responses have the ability to antagonize Th17 responses. In mouse models of allergic asthma, blockade of Th2‐effector cytokines results in elaboration of Th17 responses and associated increases in pulmonary neutrophilia. While these can be controlled by simultaneous blockade of Th17‐associated effector cytokines, clinical trials of anti‐ IL ‐17/ IL ‐17 RA blocking therapies have demonstrated increased of risk of bacterial and fungal infections. Identification of minimally effective doses of cytokine‐blocking therapies with the goal of reducing the potential emergence of infection‐related complications is a translationally relevant goal. Objective In the current report, we examine whether combined blockade of IL ‐13 and IL ‐17A, at individually sub‐therapeutic levels, can limit the development of allergic asthma while sparing expression of IL ‐17A‐associated anti‐microbial effectors. Methods House dust mite was given intratracheally to A/J mice. Anti‐ IL ‐13 and anti‐ IL ‐17A antibodies were administered individually, or concomitantly at sub‐therapeutic doses. Airway hyper‐reactivity, lung inflammation, magnitude of Th2‐ and Th17‐associated cytokine production and expression of IL ‐13‐ and IL ‐17A‐induced genes in the lungs was assessed. Results Initial dosing studies identified sub‐therapeutic levels of IL ‐13 and IL ‐17A blocking mA bs that have a limited effect on asthma parameters and do not impair responses to microbial products or infection. Subsequent studies demonstrated that combined sub‐therapeutic dosing with IL ‐13 and IL ‐17A blocking mA bs resulted in significant improvement in airway hyperresponsiveness ( AHR ) and expression of IL ‐13‐induced gene expression. Importantly, these doses neither exacerbated nor inhibited production of Th17‐associated cytokines, or IL ‐17A‐associated gene expression. Conclusion This study suggests that combining blockade of individual Th2 and Th17 effector cytokines, even at individually sub‐therapeutic levels, may be sufficient to limit disease development while preserving important anti‐microbial pathways. Such a strategy may therefore have reduced potential for adverse events associated with blockade of these pathways.