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Repeated intranasal TLR7 stimulation reduces allergen responsiveness in allergic rhinitis

Greiff, Lennart LU ; Cervin, Anders LU ; Ahlström-Emanuelsson, Cecilia LU ; Almqvist, Gun; Andersson, Morgan LU ; Dolata, Jan; Eriksson, Leif; Högestätt, Edward LU ; Kallen, Anders and Norlén, Per LU , et al. (2012) In Respiratory Research 13.
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 mu g) 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 mu g) was given once weekly for five weeks to 74 patients with allergic rhinitis out of season: starting 24 hours after... (More)
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 mu g) 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 mu g) 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 alpha(2)-macroglobulin, reflecting mast cell activity and plasma exudation, were monitored. Results: AZD8848 produced reversible blood lymphocyte reductions and dose-dependent flu-like symptoms: 30100 mu g 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 a2-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. (Less)
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keywords
Allergy, Immunity, Seasonal, Toll-like receptor 7, Treatment
in
Respiratory Research
volume
13
publisher
BioMed Central
external identifiers
  • wos:000310749900001
  • scopus:84862564782
ISSN
1465-9921
DOI
10.1186/1465-9921-13-53
language
English
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yes
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a52151a7-78dd-42fc-86e8-40ddcf4ebaf2 (old id 3256137)
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2013-01-07 09:36:28
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2017-03-05 03:07:13
@article{a52151a7-78dd-42fc-86e8-40ddcf4ebaf2,
  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 mu g) 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 mu g) 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 alpha(2)-macroglobulin, reflecting mast cell activity and plasma exudation, were monitored. Results: AZD8848 produced reversible blood lymphocyte reductions and dose-dependent flu-like symptoms: 30100 mu g 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 a2-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.},
  author       = {Greiff, Lennart and Cervin, Anders and Ahlström-Emanuelsson, Cecilia and Almqvist, Gun and Andersson, Morgan and Dolata, Jan and Eriksson, Leif and Högestätt, Edward and Kallen, Anders and Norlén, Per and Sjolin, Inga-Lisa and Widegren, Henrik},
  issn         = {1465-9921},
  keyword      = {Allergy,Immunity,Seasonal,Toll-like receptor 7,Treatment},
  language     = {eng},
  publisher    = {BioMed Central},
  series       = {Respiratory Research},
  title        = {Repeated intranasal TLR7 stimulation reduces allergen responsiveness in allergic rhinitis},
  url          = {http://dx.doi.org/10.1186/1465-9921-13-53},
  volume       = {13},
  year         = {2012},
}