Interferon-gamma as a possible target in chronic asthma.

The role of interferon-gamma (IFN-gamma) in asthma is controversial. However, this cytokine has been proposed to play a role both in acute severe asthma and chronic stable asthma. We have shown that in a chronic low-level challenge model of allergic asthma in mice, which replicates characteristic features of airway inflammation and remodelling, the mechanisms of airway hyperreactivity (AHR) are markedly different to those in short-term high-level challenge models. Notably, AHR is independent of various Th2 cytokines and their signalling pathways. However, administration of a neutralising antibody to IFN-gamma suppresses AHR. More recently, we have found that following chronic allergen challenge, but not acute challenge, IFN-gamma-producing CD4+ T cells are demonstrable in peribronchial lymph nodes, both in wild-type mice and in STAT6-/-mice. Treatment with anti-IFN-gamma decreases the number of IFN-gamma-producing CD4+ T cells in both wild-type and gene-targeted mice, providing a possible explanation for the ability of anti-IFN-gamma to inhibit AHR in the setting of chronic challenge. These data further strengthen the notion that the pathogenesis of the lesions of asthma, and especially of AHR, involves a co-operative interaction between Th2 and Th1 cytokines. This may be particularly relevant to acute exacerbations of asthma, in which setting there may be justification for therapeutic inhibition of IFN-gamma.