Background. We recently identified a common genetic variant that increases the levels of the soluble interleukin 6 receptor (sIL-6R) and is a risk factor for asthma. These results suggest that tocilizumab – a drug that blocks IL-6R and is approved to treat rheumatoid arthritis - may have therapeutic potential for asthma.

Aims. Conduct preclinical studies to validate tocilizumab for the treatment of allergic asthma.

Methods. The effect of tocilizumab treatment on the development of airway inflammation was tested using mouse models of experimental allergic asthma. We compared drug efficacy between two allergen challenge models that differ in the type of immune cells that infiltrate the lungs after challenge: cockroach (CR) model, that causes mixed granulocytic (neutrophils and eosinophils) infiltration; and house dust mite (HDM) model, which causes a predominant eosinophilic infiltration.

Results. Tocilizumab significantly attenuated allergen challenge-induced TH2/TH17 responses and associated airway inflammatory infiltration in the CR (mixed granulocytic) model of asthma. This effect was primarily mediated by inhibition of IL-17A expression by γδ-T cells. Tocilizumab had no effect in the HDM (eosinophilic) model of asthma. To understand the difference in efficacy between the two models, we measured IL-6 and sIL-6R in the airways after allergen challenge. Both allergens caused a significant increase in IL-6 levels, through an LPS/TLR4-dependent mechanism. However, CR but not HDM allergen, caused a significant increase in sIL-6R levels. These results suggest that the IL-6 trans-signalling pathway plays a critical role in CR- but not HDM-induced airway inflammation and likely explain why tocilizumab is effective in the CR but not HDM model of experimental asthma.

Conclusions. Our results validate tocilizumab as a promising new treatment for allergic asthma and suggest that high airway sIL-6R levels define a group of patients most likely to respond to treatment.