牛津剑桥The work could help the one in five people in industrialised countries with hay fever, dust, animal, or other allergies, and may also promise new treatments for those with eczema and asthma.
The new treatment strategy is possible through an increased understanding of the cells responsible for orchestrating the allergic response in humans, findings which are reported in the FASEB Journal. This has allowed the Oxford researchers to successfully block a key trigger step by focusing their efforts on drugs that target elements of the cellular processes involved.
Allergic rhinitis describes the swelling and inflammation of the lining of the nose in response to normally innocuous particles or allergens, such as pollen, house dust mites, or animal fur. This response results in cold-like symptoms and difficulty in breathing as the nasal passages narrow.
In allergic rhinitis, mast cells in the nasal lining become activated by an otherwise harmless allergen and generate an immune response. It is the resulting inflammation and swelling that gives the main symptoms experienced by allergy sufferers.
The Oxford team, along with a colleague in the Department of Ear, Nose and Throat Surgery at the John Radcliffe Hospital, Oxford, have found that, after activation of a mast cell, a feedback loop or ‘vicious circle’ leads to the recruitment and sustained activation of further mast cells.
Our results show you only need a few rogue cells to get a whole population of mast cells involved in setting off an allergic response.This knowledge allows us to develop a new strategy for treatment.
Professor Anant Parekh of the Department of Physiology, Anatomy and Genetics ‘This feedback loop keeps the whole thing going,’ says Professor Anant Parekh of the Department of Physiology, Anatomy and Genetics at the University of Oxford, who led the work. ‘We get a wave spreading through the mast cell population, activating more and more mast cells. Our results show you only need a few rogue cells to get a whole population of mast cells involved in setting off an allergic response.’
When an allergen is detected on the surface of the mast cell, calcium ions enter the cell via a protein called CRAC. The calcium ions set off a cascade of events inside the mast cell, including the release of molecules called leukotrienes. These are signalling molecules that reach other mast cells nearby and cause their CRAC proteins to allow more calcium ions in, and so keep the whole process going. The research has shown that amplification is key to sustaining mast cell activation.
'This knowledge allows us to develop a new strategy for treatment,’ says Professor Parekh. ‘We have shown you can damp down mast cell activation by taking out the CRAC protein and blocking the mast cells’ response to leukotriene molecules.’
The current best treatment for allergic rhinitis involves a steroid nasal spray, but being on steroids for a long time is not desirable.
Knowledge of the biological pathway has enabled Professor Parekh and colleagues to take a new approach that combines an existing drug that blocks leukotriene receptors and treatments that target CRAC.
The Oxford group is now working to demonstrate that this treatment would work in humans, following promising results using nasal tissue samples provided by patients with severe allergic rhinitis.
The researchers think their work may also have application for asthma. ‘We hope to make rapid progress in the area of asthma with these tools and approaches,’ says Professor Parekh
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