Thursday, August 20, 2015

Two distinct, mutually exclusive immune signatures, TH2 and TH17, determine therapy responsiveness in asthma

Asthma is a chronic condition manifested in episodes of airway hypersensitivity (inflammation, smooth muscle constriction) to innocuous signals that ordinarily would cause no tissue response in average individual. Eventually this chronic state leads to tissue remodeling and reduction of oxygen-rich air available for lung. 

Classical, allergic asthma episodes are driven by type 2 (TH2) immune response dominated by IL-4 and IL-13. However, more recently another category of asthma characterized by TH17 signature has been described. It appears that TH17 signature asthma may be more resistant to current asthma therapy.

The new study in Science Translational Medicine provided additional support for asthma stratification based on immune signature. This Genentech study showed that asthma immune profile can be stratified into mutually exclusive, non-overlapping TH2high and TH17high signatures.

This is a short paper. Basically, the authors analyzed airway gene signature from 51 asthma patients. They found that asthma patients' immune signature fall in 2 categories: either TH2high or TH17high. There is additional double negative category but its immune signature is not known.

Interestingly, both TH2high and TH17high signatures were associated with eosinophil infiltration.

Since current asthma therapies mainly target TH2 signature, the authors tested the outcome of α-IL-4/IL-13 blockade on animal asthma model (house dust mite antigen sensitization). As expected, dual blockade of TH2 cytokines significantly reduced airway inflammation.

However, TH2 cytokine blockade also induced TH17 signature, as would have been expected from in vitro studies (though it is not entirely clear from the data if this shift to TH17 pathway induced any clinically-relevant airway inflammation here).

Finally, the authors showed that blockade of both TH2 and TH17 pathways may be necessary to avoid inverse increase in TH2-driven airway hypersensitivity during anti-IL-17 therapy.

In summary, this study suggests that clinical trial design for α-IL-17 target therapy in asthma patients may need modification based on this findings. For example, α-IL-17 therapy alone may be not sufficient or that eosinophil signature could not be used as a exclusion factor for α-IL-17 therapy.

David Usharauli

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