Asthma is a heterogeneous chronic inflammatory disease and although classically considered a disease of the adaptive immune system, innate immune responses are increasingly thought to be important for disease inception and progression. A combination of genetic and environmental factors is thought to influence disease progression and the epithelium is increasingly recognised to play a key role in this process. However the molecular mechanisms underlying epithelial-immune interactions are not well understood. Several innate cytokines, such as IL-33, are released from the epithelium following either infection and/or allergen challenge and result in the production of classical Th2 cytokines seen in asthma pathogenesis. Recently described innate helper cells are produced in response to these innate epithelial cytokines and represent an early source of Th2 cytokines. We have determined that IL-33 and IL-25 contribute to the development of acute and chronic allergic pathology following inhalation of allergen. Moreover, IL-33 is a steroid resistant cytokine able to promote airway remodelling directly.
The normal response to harmless airborne allergen is tolerance and this is achieved by a complex network of cells and molecules. In contrast, asthmatic subjects respond with an acute inflammatory response which either resolves or becomes chronic. TGFb is a pivotal molecule in the development of immune responses. Its contrasting roles in promoting immune homeostasis and tolerance while being essential for wound healing indicate that TGFb plays a vital role in the development of allergic pathology in the lung. Antibody blockade of TGFb has shown variable effects according to the model system employed. In order to dissect these opposing roles of TGFb during the development of allergic immune responses we generated inducible bronchial epithelial cell specific knockouts of TGF-β1using a CCSP promoter driven Tet-on system. Mice lacking epithelial TGF-β1 displayed no baseline immune defects but on exposure to inhaled allergen exhibited diminished airway hyperactivity (AHR), BAL inflammation, eosinophilia and pulmonary Th2 cytokines. Although numbers of Th2 cells in the lung and BAL were unaffected, frequency of IL-13+ innate lymphoid cells (ILC2s) was significantly reduced. This presentation will highlight a novel interaction between ILCs and epithelial derived TGF-β as a key pathway leading to the generation of early pulmonary allergic immune responses.