A single antibody treatment for severe asthma costs the NHS tens of thousands of pounds per patient per year and must be injected in a clinic. This research aims to replace that drug with cheap, swallowable pills that could treat hay fever, food allergies, and eczema as well. The problem is that the existing treatment—an antibody that mops up allergy-triggering IgE molecules—is too expensive and cumbersome for widespread use. The researchers have already discovered where and how B-cells switch from making protective antibodies to making IgE, including that this switch can happen inside the nose. They have also found that certain bacterial molecules in asthmatic airways may drive IgE production, and that IgE itself changes shape when it triggers an allergic reaction. If this work succeeds, it could produce small-molecule inhibitors that block IgE production or prevent its shape change. Such drugs would be cheaper to manufacture, could be taken as tablets or sprays, and would work across multiple allergic conditions—not just severe asthma. The team is already collaborating with pharmaceutical companies to develop these compounds. Even if the immediate goal proves difficult, the fundamental discoveries about how B-cells switch antibody production and how IgE changes shape will open new avenues for allergy research.
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The incidence of allergic disease, and asthma in particular, has increased alarmingly in the UK and there is an urgent need for new therapies. Antibodies of a type known as immunoglobulin E (IgE) are crucially involved in the allergic response, and individuals susceptible to allergies have high IgE levels. These IgE antibodies recognise allergens that enter the airways (e.g. grass pollen), the gut (food allergens) or the skin (contact allergies), and then trigger allergic reactions. We know, from the success of an anti-IgE treatment, that removal of IgE relieves allergic symptoms. But anti-IgE, itself an antibody, is very expensive, requires administration in the clinic, and is licensed only for severe asthma. By understanding how the body produces IgE, and the way IgE activates allergic reactions, we expect to discover new ways to inhibit IgE, and develop compounds that are cheaper, more widely applicable to different allergic conditions, and easier to administer. The cells in the body that make antibodies, B-cells, switch in response to certain signals from producing beneficial, protective antibodies to producing IgE; our aim is to understand and prevent this switch. We have discovered that switching can occur in the nose rather than, as previously thought, only in lymph nodes, and now, using nasal tissue available from a surgical procedure (to clear nasal passages) developed at Guy?s Hospital, we can study the process in detail. We shall use an ultra-high resolution microscope (the first of its kind in the UK) to study events within the B-cell nucleus as the genes for IgE are switched on, and then study the survival and proliferation of these IgE-producing cells. This work will undoubtedly identify new targets for intervention. We have also discovered that ?superantigens?, bacterial molecules that trigger antibody production, are present in asthmatic patients? airways. We believe that these superantigens may promote IgE production, in the lung or nose, and will study how they interact with IgE ? opening up a new approach to allergy treatment. We will also investigate the claim that certain IgE molecules are more active than others in triggering allergy. We have already determined the molecular structure of IgE and found that it changes its shape when it triggers an allergic reaction. We can now test compounds that prevent this change in shape, collaborating with the pharmaceutical industry to develop small-molecule inhibitors that overcome the limitations of anti-IgE.
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