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

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 techniques

Our 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.

AIMS
1) To investigate the pathophysiology of acute allergic reactions to peanut, and how this relates to severity of clinical symptoms, by assessing mucosal absorption of allergen, cellular activation and vascular physiology.
2) To understand the process by which exercise may alter the character of food allergic reactions.

METHODS
This fellowship will capitalize on a recently funded trial involving repeated double-blind placebo-controlled food challenge (DBPCFC) of peanut-allergic adults under controlled conditions. We will assess mechanisms of the acute reaction to a food allergen through:
- assays for biomarkers (blood, saliva, urine) including kinins, complement, leukotrienes and mast cell proteases. Leukocyte activation will be determined by poylchromatic flow cytometry
- Assessment of local and systemic changes in vascular flow and permeability, using established non-invasive techniques
- the above techniques will be repeated with DBPCFC after exercise

SCIENTIFIC AND MEDICAL OPPORTUNITIES
1) Investigate how the pathophysiology of acute allergic reactions to food differs from that of non-food triggers, which are not often associated with systemic effects. This will highlight new targets for future therapeutic interventions, as well as facilitate risk stratification of peanut allergic individuals
2) Determine the extent to which animal models of food allergy are applicable to man.
3) Allow for characterisation of peanut allergic individuals in terms of peanut-specific antibody production (IgE, IgG, IgG4, IgA, free Ig light chain) and how this relates to reaction severity
4) Validation of novel salivary markers of allergic reactions, improving diagnostic opportunities in patients in whom diagnosis is unclear
5) Synergistic collaborations with the pan-European project on Integrated Approaches to Food Allergen and Allergy Risk Management (iFAAM), which will investigate intrinsic and extrinsic factors affecting the severity of reactions to foods.

1. Health and Social Outputs : Individuals

Study participants: will benefit directly from an awareness of their symptoms and the amount of food allergen needed to trigger this. Previous studies have demonstrated that patients undergoing diagnostic food challenges report an improvement in quality of life measures within a short timeframe (months), even where the challenge is 'positive'.

Patients and their families: Up to 8% of children and 2% of adults in the UK have food allergies; this has a high impact on a patient's quality of life, along with their carers (e.g. parents of affected children). This study will complement the results from the threshold-determining study, by providing additional data relating to the allergic reaction, and whether levels of exposure around the threshold cause reproducible reactions in terms of symptom severity. This will inform policy relating to allergen labelling of foods in terms of potential cross-contamination, resulting in benefits to the wider food-allergic population in the UK. It is hoped that this will take place within 3-5 years. Longer-term, the study will highlight future therapeutic targets which may be useful in the future management of severe reactions.

Health professionals: will be better able to offer reassurance to those affected by food allergies, on the basis of a greater understanding of mechanisms involved and improved tools to determine who is at risk of severe symptoms. The validation of diagnostic techniques for food allergic reactions (e.g. salivary testing) will be of particular utility for professionals in the emergency services and A&E departments. These benefits should commence within the period of this grant, once results have been published in peer-reviewed journals.

2. Health and Social Outputs : Public Services and Health Policy

UK & Europe Policy makers: The results will be used to inform data relating to Minimal Eliciting Doses for the food-allergic population and the required safety factor, in order to inform industry and with a view to protecting the allergic population. This has been determined to be a priority by the Food Standards Agency (FSA). Through my proposed collaboration in the EU-funded project on Integrated Approaches to Food Allergen and Allergy Risk Management (iFAAM), there will also be significant benefits to EU policy makers.

Health policy: Improved risk stratification of peanut-allergic individuals will allow a more targeted provision of education and rescue medications (such as adrenaline autoinjector devices), with associated cost benefits.

Voluntary sector: A number of support groups and charities have been established to support food-allergic patients and their families. Food allergy has a high impact on quality of life measures. By providing information relating to risk assessment and allergen avoidance, the study will empower these groups to provide more comprehensive information to allergic individuals in the UK, within a timeframe similar to that of the publication of the study results (as described above).

3. Economic benefits : National and Global

Food allergy is increasing throughout the world, and is now a global issue, particularly with the export of foods from one country to another. Some countries (e.g. Australia) have already attempted to rationalise allergen labelling of foods in order to provide clearer information to consumers, though the success of this initiative is debatable. Europe, and in particular the FSA, are taking a more quantitative, evidence-based approach. In conjunction with good manufacturing practice, this initiative can be expected to provide a competitive advantage in the provision of foods with appropriate labelling for allergy sufferers. European researchers are leading the world in advancing this important area of investigation.