A limited CpG-containing oligodeoxynucleotide therapy regimen induces sustained suppression of allergic airway inflammation in mice
- John D Campbell1,
- Sariah A Kell1,
- Heather M Kozy1,
- Jeremy A Lum1,
- Rosemary Sweetwood1,
- Mabel Chu1,
- Cameron R Cunningham1,
- Hugh Salamon2,
- Clare M Lloyd3,
- Robert L Coffman1,
- Edith M Hessel1
- 1Dynavax Technologies, Berkeley, California, USA
- 2Knowledge Synthesis, Berkeley, California, USA
- 3Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London, UK
- Correspondence to Dr John D Campbell, Dynavax Technologies, 2929 7th St, Ste 100, Berkeley, CA 94710, USA;
- Received 3 October 2013
- Revised 24 December 2013
- Accepted 9 January 2014
- Published Online First 24 January 2014
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.