Mechanisms underlying the physiological and cellular response to food allergen challenge in human subjects with peanut allergy

点击翻译按钮获取中文摘要

Food allergy affects up to 2% of adults and 8% of children in the UK, and can cause life-threatening reactions (anaphylaxis) in some but not all individuals. The mainstay of management remains dietary avoidance. There is no effective treatment for preventing allergic reactions, which can be fatal even when rescue medication is given in a timely manner.Allergic reactions to food are mediated through the Immunoglobulin E (IgE) antibody. The binding of allergenic proteins in food to IgE causes the release of different chemical mediators, including histamine. Much of our knowledge of the mechanism is derived from animal models, but this may not be representative of the situation in man. Antihistamines can prevent fatality in animal models of anaphylaxis but are much less effective in man, possibly because humans are 1000-fold more sensitive to the effects of histamine than, for example, mice. Furthermore, anaphylaxis in peanut-allergic humans can be triggered by tiny amounts of protein (under 10mg or 1/30 of a single peanut). By comparison, very high levels are required to cause anaphylaxis by the oral route in mouse models, equivalent to a person eating over 1000 peanuts. These examples demonstrate the difficulties of extrapolating data from animal models to man.The diagnosis of food allergy can be confirmed by the detection of specific IgE to the trigger food, either by blood or skin testing. Unfortunately, while levels of specific IgE predict the likelihood of reaction after exposure, they do not predict the severity of reaction. While some risk factors have been identified for anaphylaxis (e.g. asthma, underlying heart disease, previous anaphylaxis), the majority of patients do not have a risk factor. Health professionals are therefore unable to determine who is at risk of anaphylaxis, resulting in widespread prescribing of adrenaline auto-injector pens for emergency rescue treatment. The prescription of these devices has increased over the past decade, from 74,600 devices in England in 2000 to over 230,000 devices in 2010, at a cost of £12.5m. The vast majority of these devices are never used, and their prescription is a significant cost to the health service. Any data facilitating improved risk stratification of allergic individuals would assist health professionals in providing reassurance to patients and parents alike, as well as delivering economic savings.Given the importance of dietary avoidance in the management of food allergies, the Food Standards Agency (FSA) is commissioning a study to determine the amount of peanut which needs to be consumed to trigger a reaction. This threshold varies significantly between individuals, but also within the same person, depending on a number of poorly understood factors including exercise. The aim is to define a safe level of potential food contamination below which peanut-allergic individuals will not react, thus informing the food industry and better protecting the allergic population. The study will recruit 100 peanut-allergic volunteers, each undergoing controlled exposure to peanut or placebo under medical supervision on different occasions.The FSA study provides a unique opportunity to assess the mechanism of food allergic reactions, and determine the extent to which data from animal models are applicable to man. We propose to monitor the effects of food allergic reactions on:- the absorption of food proteins in the mouth, to see if this changes as the reaction progresses- the release of different chemical mediators in blood, saliva and urine.- changes in blood flow, both at the site of reaction and beyond, using non-invasive techniquesOur data will provide valuable insight into the mechanisms underlying food allergic reactions in man, highlighting new targets for future diagnostic tests and therapies. We further plan to develop new strategies to improve risk stratification, in order to improve management of peanut allergic individuals.