NILTHERA · Novel Interleukins for immunotherapy of Asthma

Novel interleukins for immunotherapy of asthma

Respiratory diseases associated with allergy such as asthma and rhinitis constitute a major and continuously growing public health concern for Europe. More than 30 million European citizens suffer from chronic asthma, among which 6 million have severe symptoms and 1.5 million live in fear of dying from an asthmatic attack. A large number of these patients are also children. The economic burden of asthma is major. Asthma costs EUR 17.7 billion per year to European healthcare authorities and another EUR 9.8 billion per annum to the European economy due to absenteeism from work and productivity loss (European Respiratory Society White Book, 2003). Allergic asthma is a chronic inflammatory disease of the airways characterised by T helper two (Th2) mediated immune responses to common aeroallergens in genetically susceptible individuals. Th2 responses most frequently develop early in life, persist even during asymptomatic periods and are exacerbated in response to environmental triggers such as allergens, viral infections or other irritants leading to recurrent episodes of wheezing, breathlessness and coughing and eventually the progressive decline of lung function. Although the inflammatory cascade inducing and/or exacerbating an allergic response in the airways is complex and largely unexplored, several innate immunity cytokines such as thymic stromal lymphopoietin (TSLP), interleukin 25 (IL-25) and IL-33 have been recently shown to be crucial for up-regulating Th2-mediated immune responses and triggering asthmatic symptoms. However, the role of other potentially important innate immunity cytokines such as type III interferons has not been addressed. In the present study, we evaluated the role of interleukins-28/29, also termed type III IFNs or lambda interferons (IFN?/IL-28s), in the development of allergic airway inflammation. Using genetically engineered mice deficient in IL-28R signalling, transgenic expression of IL-28A and recombinant IL-28A treatment, we found that endogenous IL-28 cytokines are critical for driving Th1 cell differentiation while limiting Th2 cell generation in vivo. Accordingly, IL-28Ra-/- mice developed exacerbated allergic airway inflammation and hyper-responsiveness associated with augmented Th2 responses. In addition, transgenic expression of IL-28A or recombinant IL-28A treatment of wild-type mice up-regulated Th1 responses in vivo, leading to suppression of Th2-mediated inflammation in the airways and Th2-mediated disease. IL-28-induced immune shifting to a Th1 cytokine profile was mediated through the modulation of dendritic cell (DC) function rather than direct effect on T cells. Transcriptional profiling analysis of IL-28-treated DCs revealed several established molecular pathways leading to Th1 polarisation. To further study the biology of IL-28 cytokines in vivo and unwind their therapeutic potential in allergic asthma, we generated a novel IL-28a/eGFP knock-in reporter mouse. This makes possible the mapping of IL-28 expression in a spatiotemporal manner and the screening of existing and novel agonists for inducing IL-28 cytokines and treating allergic asthma. Taken together our findings demonstrate a critical role of IL-28 cytokines in controlling T cell responses in vivo and support the therapeutic application of recombinant IL-28 or IL-28-inducing agonists for the treatment of allergic asthma and allergic asthma exacerbations.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз