Final Report Summary - NILTHERA (Novel interleukins for immunotherapy of asthma)
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.