A limited CpG-containing oligodeoxynucleotide therapy regimen induces sustained suppression of allergic airway inflammation in mice.
BACKGROUND
CpG-containing oligodeoxynucleotides (CpG-ODNs) are potent inhibitors of T helper 2 mediated allergic airway disease in sensitised mice challenged with allergen. A single treatment has transient effects but a limited series of treatments has potential to achieve clinically meaningful sustained inhibition of allergic airway disease.


OBJECTIVE
To optimise the treatment regimen for sustained efficacy and to determine the mechanisms of action in mice of an inhaled form of CpG-ODN being developed for human asthma treatment.


METHODS
We set up a chronic allergic-asthma model using ragweed-sensitised mice exposed weekly to intranasal ragweed. Using this model, the effects of a limited series of weekly intranasal 1018 ISS (CpG-ODN; B-class) treatments were evaluated during treatment and for several weeks after treatments had stopped but weekly allergen exposures continued. Treatment efficacy was evaluated by measuring effects on lung T helper 2 cytokines and eosinophilia, and lung dendritic cell function and T-cell responses.


RESULTS
Twelve intranasal 1018 ISS treatments induced significant suppression of bronchoalveolar lavage eosinophilia and interleukin 4, 5 and 13 levels. This suppression of allergic T helper 2 parameters was maintained through 13 weekly ragweed exposures administered after treatment cessation. Subsequent experiments demonstrated that at least five treatments were required for lasting suppression. Although CpG-ODN induced moderate T helper 1 responses, suppression of allergic airway disease did not require interferon γ but was associated with induction of a regulatory T-cell response.


CONCLUSIONS
A short series of CpG-ODN treatments results in sustained suppression of allergic lung inflammation induced by a clinically relevant allergen.
Dynavax Technologies, Berkeley, CA 94710.
John D
JD
Campbell
Dynavax Technologies, Berkeley, CA 94710.
Sariah A
SA
Kell
Dynavax Technologies, Berkeley, CA 94710.
Heather M
HM
Kozy
Dynavax Technologies, Berkeley, CA 94710.
Jeremy A
JA
Lum
Dynavax Technologies, Berkeley, CA 94710.
Rosemary
R
Sweetwood
Dynavax Technologies, Berkeley, CA 94710.
Mabel
M
Chu
Dynavax Technologies, Berkeley, CA 94710.
Cameron R
CR
Cunningham
Knowledge Synthesis, Berkeley, CA 94710.
Hugh
H
Salamon
Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ UK.
Clare M
CM
Lloyd
Dynavax Technologies, Berkeley, CA 94710.
Robert L
RL
Coffman
Dynavax Technologies, Berkeley, CA 94710.
Edith M
EM
Hessel
D000485:Allergens; D031164:Ambrosia; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005260:Female; D008168:Lung / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage*; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000517:prevention & control*; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology
D000485:Allergens; C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides
Allergic Lung Disease; Asthma; Asthma Pharmacology; Innate Immunity