Abstract
BackgroundAlthough allergic asthma is a complex area with many interacting factors involved, the ‘hygiene hypothesis’ proposes that a lack of exposure to infection during childhood may polarise the immune system towards allergen-reactive Th2-type responses in genetically susceptible individuals. Toll-like receptors (TLRs) play a key role within the innate immune system and TLR7 agonists have previously been shown to up-regulate Th1 responses and down-regulate Th2 responses to allergens in murine models of allergic or chronic asthma. This study aimed to examine the efficacy and safety of the novel TRL7 agonist AZD8848, which has been developed as an antedrug.MethodsIn this double-blind, randomised, parallel-group study, AZD8848 60 μg or placebo was administered intranasally once-weekly for 8 weeks in patients with mild-to-moderate allergic asthma (NCT00999466). Efficacy assessments were performed at 1 and 4 weeks after the last dose. The primary outcome was the late asthmatic response (LAR) fall in forced expiratory volume in 1 s (FEV1) after allergen challenge at 1-week post-treatment.ResultsAZD8848 significantly reduced average LAR fall in FEV1 by 27% vs. placebo at 1 week after treatment (p = 0.035). This effect was sustained at 4 weeks post-treatment; however, it did not reach clinical significance. AZD8848 reduced post-allergen challenge methacholine-induced airway hyper-responsiveness (AHR) vs. placebo at 1 week post-dosing (treatment ratio: 2.20, p = 0.024), with no effect at 4 weeks. There was no significant difference between the two groups in plasma cytokine, sputum Th2 cytokine or eosinophil responses post-allergen challenge at 1 week after treatment. The incidence of adverse events was similar in the two groups. AZD8848 was generally well tolerated.Conclusions and clinical relevanceIn patients with allergic asthma, TLR7 agonists could potentially reduce allergen responsiveness by stimulating Type 1 interferon responses to down-regulate the dominant Th2 responses.Trial registrationclinicaltrials.gov identifier NCT00999466.
Highlights
Allergic asthma is a complex area with many interacting factors involved, the ‘hygiene hypothesis’ proposes that a lack of exposure to infection during childhood may polarise the immune system towards allergen-reactive T-helper cells (Th2)-type responses in genetically susceptible individuals
The ‘hygiene hypothesis’ proposes that a reduction in T-helper 1 cells (Th1) or T regulatory (Treg)-like responses resulting from lack of exposure to infection during childhood may polarise the immune system towards allergen-reactive Th2-type responses in genetically susceptible individuals
For inclusion in the main part of the study, patients had to demonstrate forced expiratory volume in 1 s (FEV1) > 70% of predicted normal; an early asthmatic response (EAR) corresponding to ≥20% decrease in FEV1 within 2 h and a late asthmatic response (LAR) corresponding to ≥15% decrease in FEV1 between 4 and 10 h post-allergen challenge on 2 consecutive occasions and a methacholine provocation concentration leading to a 20% reduction in FEV1 (PC20) < 16 mg/mL
Summary
Allergic asthma is a complex area with many interacting factors involved, the ‘hygiene hypothesis’ proposes that a lack of exposure to infection during childhood may polarise the immune system towards allergen-reactive Th2-type responses in genetically susceptible individuals. The ‘hygiene hypothesis’ proposes that a reduction in Th1 or Treg-like responses resulting from lack of exposure to infection during childhood may polarise the immune system towards allergen-reactive Th2-type responses in genetically susceptible individuals. Th2 cells respond to environmental antigens by secreting a range of cytokines, including interleukin (IL)-4, IL-5, IL-9 and IL-13 [7] Such responses can be suppressed by Treg cells through the secretion of the anti-inflammatory cytokine IL-10 [9] and type II interferon gamma (IFNγ) secreted by Th1 cells [10]
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