Late Breaking Abstract - Effects of tezepelumab on host epithelial tolerance to virus in patients with uncontrolled asthma

Abstract

<b>Background:</b> Tezepelumab, an anti-TSLP mAb, reduces asthma exacerbations but the mechanisms remain unclear. Human bronchial epithelial cells (HBECs) are major producers of antiviral IFNβ as well as alarmins (TSLP and IL33) and Type2 (T2) cytokines that likely contribute to viral induced exacerbations. <b>Aim:</b> We hypothesized that tezepelumab therapy improves host tolerance to virus by decreasing inflammatory alarmins/cytokines without affecting anti-viral resistance. <b>Methods:</b> Bronchoalveolar lavage (BAL) and HBECs were obtained bronchoscopically from patients with uncontrolled asthma at baseline and after 12 weeks’ therapy with tezepelumab 700mg 4-weekly (n=13) or placebo (n=13) (NCT02698501). HBECs were cultured and exposed to viral infection mimic poly(I:C) or rhinovirus (RV) infection. Alarmins, cytokines and IFNβ were analysed by RTqPCR and multiplex ELISA. <b>Results:</b> IL33 was decreased in unstimulated HBECs in tezepelumab treated patients, correlating with lower IL33 gene expression in BAL (p&lt;0.001 baseline vs post treatment). Tezepelumab also decreased IL33 expression when HBECs were stimulated with poly(I:C) or infected with RV (p&lt;0.05). Poly(I:C) increased IL4 and IL13 release/expression from HBEC and this response was dampened by tezepelumab (p&lt;0.05). This was not seen with poly(I:C)- or RV-induced IFNβ. Importantly, the alterations in cytokine expression were not seen in the placebo group. <b>Conclusion:</b> Blocking TSLP in uncontrolled asthma reduces epithelial IL33 as well as T2 cytokines in response to viral stimulation, whereas IFNβ is not affected. The data suggest that TSLP regulates host tolerance to virus which could explain in part the effect of tezepelumab on asthma exacerbations.