Abstract
BackgroundInteractions between Th1 and Th2 immune responses are of importance to the onset and development of allergic disorders. A Toll-like receptor 7 agonist such as AZD8848 may have potential as a treatment for allergic airway disease by skewing the immune system away from a Th2 profile.ObjectiveTo evaluate the efficacy and safety of intranasal AZD8848.MethodsIn a placebo-controlled single ascending dose study, AZD8848 (0.3-600 μg) was given intranasally to 48 healthy subjects and 12 patients with allergic rhinitis (NCT00688779). In a placebo-controlled repeat challenge/treatment study, AZD8848 (30 and 60 μg) was given once weekly for five weeks to 74 patients with allergic rhinitis out of season: starting 24 hours after the final dose, daily allergen challenges were given for seven days (NCT00770003). Safety, tolerability, pharmacokinetics, and biomarkers were monitored. During the allergen challenge series, nasal symptoms and lavage fluid levels of tryptase and α2-macroglobulin, reflecting mast cell activity and plasma exudation, were monitored.ResultsAZD8848 produced reversible blood lymphocyte reductions and dose-dependent flu-like symptoms: 30–100 μg produced consistent yet tolerable effects. Plasma interleukin-1 receptor antagonist was elevated after administration of AZD8848, reflecting interferon production secondary to TLR7 stimulation. At repeat challenge/treatment, AZD8848 reduced nasal symptoms recorded ten minutes after allergen challenge up to eight days after the final dose. Tryptase and α2-macroglobulin were also reduced by AZD8848.ConclusionsRepeated intranasal stimulation of Toll-like receptor 7 by AZD8848 was safe and produced a sustained reduction in the responsiveness to allergen in allergic rhinitis.Trial registrationNCT00688779 and NCT00770003 as indicated above.
Highlights
Interactions between Th1 and Th2 immune responses are of importance to the onset and development of allergic disorders
Th1-mediated immunity may be defective in a modern clean environment resulting in facilitation of Th2 responses associated with allergic disorders [2,3]
Toll-like receptor (TLR) are receptors of the innate immune system that recognise conserved microbial components known as pathogen-associated molecular patterns (PAMPs) [5]
Summary
Interactions between Th1 and Th2 immune responses are of importance to the onset and development of allergic disorders. A Toll-like receptor 7 agonist such as AZD8848 may have potential as a treatment for allergic airway disease by skewing the immune system away from a Th2 profile. TLRs are receptors of the innate immune system that recognise conserved microbial components known as pathogen-associated molecular patterns (PAMPs) [5]. Activation of TLRs stimulates the innate immune system, potentially leading to down regulation of Th2 adaptive responses to allergen [6]. The possibility of skewing the immune system away from a Th2 response, as has been attempted previously by other measures [7,8,9,10], is the basis for the development of TLR agonists as treatments for allergic rhinitis and asthma
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