PT - JOURNAL ARTICLE AU - Lennart Greiff AU - Cecilia Ahlstrom-Emanuelsson AU - Gun Almqvist AU - Morgan Andersson AU - Anders Cervin AU - Jan Dolata AU - Leif Eriksson AU - Anders Kallen AU - Per Norlen AU - Inga-Lisa Sjolin AU - Henrik Widegren TI - Repeated intranasal TLR7 stimulation reduces allergen responsiveness in allergic rhinitis DP - 2011 Sep 01 TA - European Respiratory Journal PG - p1843 VI - 38 IP - Suppl 55 4099 - http://erj.ersjournals.com/content/38/Suppl_55/p1843.short 4100 - http://erj.ersjournals.com/content/38/Suppl_55/p1843.full SO - Eur Respir J2011 Sep 01; 38 AB - Background: The TLR7 agonist AZD8848 was developed as a treatment for allergic airway disease with the rationale of suppressing allergic (Th2-like) immune responses by triggering innate immune responses through TLRs. Intranasal administration of AZD8848 has demonstrated protection against allergen challenge in animal models of asthma and allergic rhinitis. AZD8848 is rapidly hydrolysed in vivo to a metabolite that is over 100-fold less active, to minimise the risk of undesirable systemic effects.Methods: Five once-weekly intranasal doses of AZD8848 (60 μg) were given in a randomised, placebo-controlled, double-blind, parallel group clinical trial to patients with allergic rhinitis (AR) off season (NCT00770003). Nasal symptoms were recorded during a 7-day nasal allergen challenge period starting 24 hours post last dose of AZD8848 to assess clinical effect. Biomarkers of TLR7 activation and plasma exudation were monitored in plasma or nasal lavage. Safety, tolerability and pharmacokinetics were also monitored.Results: Successful stimulation of TLR7 was indicated by reversible reductions in blood lymphocytes and increased plasma levels of IL-1Ra 24 hrs after administration of AZD8848. Some patients reported transient flu-like symptoms, as expected based on mechanism of action. AZD8848 reduced total nasal symptoms of allergic rhinitis as recorded 10 minutes after allergen challenge on days 5, 6, 7 and 8 after the last dose of AZD8848. Levels of α2-macroglobulin in nasal lavage were also reduced by AZD8848.Conclusion: Repeated intranasal administration of AZD8848 activated TLR7 and this resulted in a sustained reduction in responsiveness to allergen in patients with AR.