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.