Repeated intranasal TLR7 stimulation reduces allergen responsiveness in allergic rhinitis

Greiff, Lennart, Cervin, Anders, Ahlstrom-Emanuelsson, Cecilia, Almqvist, Gun, Andersson, Morgan, Dolata, Jan, Eriksson, Leif, Hogestatt, Edward, Kallen, Anders, Norlen, Per, Sjolin, Inga-Lisa and Widegren, Henrik (2012) Repeated intranasal TLR7 stimulation reduces allergen responsiveness in allergic rhinitis. Respiratory Research, 13 53.1-53.10. doi:10.1186/1465-9921-13-53


Author Greiff, Lennart
Cervin, Anders
Ahlstrom-Emanuelsson, Cecilia
Almqvist, Gun
Andersson, Morgan
Dolata, Jan
Eriksson, Leif
Hogestatt, Edward
Kallen, Anders
Norlen, Per
Sjolin, Inga-Lisa
Widegren, Henrik
Title Repeated intranasal TLR7 stimulation reduces allergen responsiveness in allergic rhinitis
Journal name Respiratory Research   Check publisher's open access policy
ISSN 1465-9921
1465-993X
Publication date 2012-06-22
Sub-type Article (original research)
DOI 10.1186/1465-9921-13-53
Open Access Status DOI
Volume 13
Start page 53.1
End page 53.10
Total pages 10
Place of publication London, United Kingdom
Publisher BioMed Central
Language eng
Formatted abstract
Background: 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.

Objective: To evaluate the efficacy and safety of intranasal AZD8848.

Methods: In 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 α 2-macroglobulin, reflecting mast cell activity and plasma exudation, were monitored.

Results: AZD8848 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 α 2-macroglobulin were also reduced by AZD8848.

Conclusions: Repeated 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 registration: NCT00688779 and NCT00770003 as indicated above. 
Keyword Allergy
Immunity
Seasonal
Toll-like receptor 7
Treatment
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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