Therapy including Immunomodulation

Lavender and Lee discovered a new mechanism for GR repressive activity by GR binding to NFAT/AP1 sites and then recruiting co-repressor complexes that suppress GATA3 mediated activation. Corrigan, Sun and Lee identified expression of TSLP and Th2 T cell attracting chemokines in the bronchial mucosa in asthma and COPD. They also further explored the pro-inflammatory properties of the Th2 memory-potentiating cytokine IL-25, showing that it acts on vascular endothelial cells to promote angiogenesis by inducing secondary VEGF production, a process which is dependent on PI3 kinase and MEK/ERK kinase signalling, highlighting these molecules as potential molecular targets in asthma. Hawrylowicz has shown that GCs fail to induce IL-10-synthesising human T regulatory cells in GC resistant patients which can be overcome by Vitamin D3. This exciting work has been extended into an exploratory clinical study to investigate whether Vitamin D3 supplementaion increases the clinical response of severe asthmatics to systemic glucocorticoid therapy. This may uncover further novel therapeutic strategies for asthma, for example by using Vitamin D analogues without calcium regulatory activity. Santis' studies suggest a critical role for alpha v beta 1 integrin in epithelial binding and internalisation of Adenovirus 5. Based on the structure of one of the adenovirus capsid proteins, he has designed novel constructs for cell type specific adenovirus targeting. Noble defined a distinct subset of CD8 regulatory T cells which prevent primary T cell responses to inhaled allergen.

Further work will investigate how regulatory T cell responses can be induced at the lung mucosal surface through novel immunotherapeutic approaches including the use of a potent MHC Class I-restricted peptide vaccine which inhibits Th2-mediated allergic lung inflammation. Corrigan's preseasonal immunotherapy trials have informed clinical management. A new trial performed with Allergy therapeutics suggests that preseasonal therapy with grass pollen vaccine given with the Toll-like receptor 4 stimulant MPL allows for fewer injections while retaining efficacy. A number of Centres have modified their regimens for the treatment of tree and grass pollen sensitive seasonal rhinoconjunctivitis to a pre-seasonal regimen which is more convenient for and therefore preferred by patients. Lack has found that immunotherapy to grass pollen reduced symptoms and medication in children with allergic asthma by 50 per cent. His studies will form the basis for an MHRA application for a license to treat children with immunotherapy to grass pollen.

Lee and Corrigan will continue to elucidate mechanisms for refractory asthma phenotypes including glucocorticoid resistant and aspirin sensitive respiratory disease as well as severe, non-atopic asthma. A large study of prostanoid metabolism and a systematic study of the effects of PGE2 on its four receptors in aspirin sensitive patients has recently been completed and is awaiting analysis. A novel ex vivo model using cultured nasal polyps form aspirin sensitive patients is also being utilised to explore direct effects of aspirin and other COX-1, as well as COX-2 inhibitors on eicosanoid release ex vivo. A study of the effects of humanised, monoclonal anti-IgE antibody in non-atopic asthmatics, based on observations of de novo IgE switching and synthesis in the bronchial mucosa of these patients is set to commence. Hawrylowicz's group, while testing whether vitamin D3 has steroid sparing effects clinically, will continue analysis of the biochemical mechanisms involved and identification of surrogate markers. She will collaborate with Lavender and Cousins on molecular profiling of human IL-10-Treg cells. Santis will exploit the increased availability of active alpha v beta 1 integrin in airway inflammation to explore the use of different Ad serotypes to transduce antigen-presenting cells to shift Th2 towards regulatory T cell phenotypes. Corrigan and Lee will test novel biologics as they become available. These will include novel antibodies directed against chemokine receptors as well as key cytokines implicated in airways remdelling in asthma. Noble will develop MHC class I-restricted peptide vaccines and Corrigan will be testing sublingual immunotherapy with house dust mite extract for treatment of perennial allergic rhinoconjunctivitis and asthma (with ALK-Abello). He will assess whether the treatment has disease modifying properties.