BIOMARKERS AND MECHANISMS OF FOOD ALLERGY AND ORAL TOLERANCE IN IgE-SENSITISED CHILDREN

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The symptoms of food allergy (FA) result from the release of certain substances by cells of the immune system, called mast cells and basophils, triggered by the interaction between allergy antibodies and food allergens. FA is often diagnosed using skin prick test or by detecting IgE (allergy antibodies) in the blood. However, more common than being food allergic is to have a positive allergy test to that food. For example, only 1 out of 5 children with a positive allergy test to peanut in the United Kingdom has peanut allergy. In the equivocal cases (more than 50% of patients), an oral food challenge (OFC) is required. OFC consists in giving the patient the suspected food in a controlled environment to see whether the patient develops an allergic reaction. OFC are quite expensive, time-consuming and place the patient at risk of a potentially severe reaction, but this is currently the gold-standard for the diagnosis of FA. In my MRC-funded PhD project, I developed a new blood test called the basophil activation test (BAT) that works like an OFC in a test tube. BAT to peanut showed 97% accuracy in the diagnosis of peanut allergy and reduced the need for OFC by two thirds. In this project, I will develop similar diagnostic tests for cow's milk and egg allergies, which are the most common food allergies in childhood, and for sesame and cashew, which are two of the foods that most commonly require OFC as conventional allergy tests fail to diagnose allergy correctly. I anticipate that BAT will lead to a significant improvement of care for allergic patients and will reduce the costs and anxiety associated with OFC.BAT requires the use of fresh blood cells. As part of an MRC Award, I developed a test similar to BAT using a cell line that is grown in the laboratory and thus is readily available. I will test various samples of peanut allergic and non allergic patients to validate this assay as a biomarker of peanut allergy. I have developed a similar assay to test the ability of antibodies in the blood of non allergic patients to block IgE - this is the inhibition of mast cell activation test (IMAT), that I will validate as a biomarker of food tolerance. These assays could be used in future studies to test samples collected far from the laboratory or to test in parallel samples that have been collected at different time points, in relation to allergy or tolerance.To understand why some patients have a positive allergy test and are not allergic, I will determine which specific part of the allergen the antibodies of allergic patients and non allergic individuals recognise. It is possible that allergic and tolerant patients recognise different parts of the allergen that may or may not be able to trigger allergic symptoms, respectively. It is also possible that allergic and tolerant patients recognise the same parts of the allergen molecule but tolerant individuals generate antibodies of a different type that are able to block IgE. In collaboration with Professors Brian Sutton and Hannah Gould, artificial antibodies will be generated based on the antibodies of a peanut allergic patient and a crystal formed by these antibodies and by peanut allergens will help to investigate which part of the allergen is recognised by the IgE allergy antibodies. Mutant allergens will be generated by changing the allergen at specific sites. I will be testing these mutant allergens alongside with naturally occurring peanut allergens regarding their ability to cause allergic symptoms in the MAT. Blocking antibodies directed at the same part of the peanut allergens will be generated and its blocking activity tested on the IMAT. Understanding precisely what is happening when a patient is allergic and when a patient is not allergic despite the presence of IgE antibodies will help us to find ways to treat patients with FA and to prevent the development of FA by modifying the way the immune system responds to peanut or other food allergens.