The effect of T2-targeted biologicals on eicosanoids
Ample evidence from clinical trials showing effectiveness of drugs targeting T2-inflammation (targets include IgE and the cytokines IL5, IL4, and IL13) on asthma exacerbations, as well as improvements in symptoms and disease severity in chronic rhinosinusitis with nasal polyps (CRSwNP),158,159 underscored the involvement of T2-inflammation in these conditions.160,161 As mentioned above, the majority of asthma exacerbations are precipitated by respiratory viruses (esp. RSV and RV),162 while in sensitized subjects, allergen exposure may enhance virally-triggered exacerbations due to synergistic interaction through joint mechanisms including the T2-inflammatory pathway.162-165 Both viral and allergen-triggered pathways include several inflammatory and immune (effector) cells, such as mast cells, basophils, Th2 cells, ILCs, macrophages, neutrophils and eosinophils. Many of these cells are capable of releasing eicosanoids upon activation and/or possess one or more eicosanoid receptors,166 thus contributing to the exacerbation and its sequelae (e.g. bronchoconstriction, airway inflammation, bronchial hyperresponsiveness).167 In CRSwNP the T2-inflammatory pathway is also triggered by several stimuli such as viruses, bacteria and allergens, which stimulate inflammatory cell- and cytokine-mediated pathomechanisms in the nasal and paranasal mucosa.161
Although in vitro data indicate that biologicals may influence eicosanoid pathways in mast cells and basophils,168 so far there are no published data on direct effects of T2-targeted biologicals on the synthesis or release of eicosanoids in humansin vivo (Fig. 4) . However, it makes sense that, by blocking pathways and cells (esp. mast cells, basophils, eosinophils and neutrophils) responsible for the release of these pro-inflammatory mediators, may consequently also reduce eicosanoid levels. In addition, previous evidence from clinical studies in asthma showed (partial) reduction of both allergen- and virus-induced airway responses and asthma exacerbations by selective eicosanoid antagonists.48,118,119,169,170,171 Besides, clinical studies on biologicals in CRSwNP also included a representative cohort of patients with NERD and also found a good clinical response158 as well as a reduced T2-biomarker profile in this subpopulation.172 However, so far there are no data on the direct effect of T2-biologicals on the individual eicosanoids nor head-to-head studies comparing biologicals with selective eicosanoid blockers or combinations.