Abstract and Introduction
Abstract
Purpose of Review: Food allergy is a serious and growing problem. Although the current standard of care for patients with food allergies is based on avoidance of the trigger, increased understanding of the mechanisms involved in oral tolerance has shifted focus of treatment and prevention toward inducing tolerance. Here we discuss the relationship of food allergy to oral tolerance and review recent oral tolerance studies, focusing on the mechanistic role of antigen presenting cells and the generation of regulatory T cells in mice and humans.
Recent Findings: Specialized intestinal antigen presenting cells are conditioned by spatial and soluble microenvironmental factors to promote tolerance to dietary antigen primarily via the induction of regulatory T cells. Retinoic acid, a vitamin A metabolite, has been recently identified as a key environmental factor in this process.
Summary: Future clinical trials for food allergy immunotherapy will benefit from approaches, which target the oral tolerance pathways currently being elucidated.
Introduction
Food allergy affects 6% of children younger than 3 years of age and approximately 4% of adults in the United States. A recent report from the Centers for Disease Control confirmed these figures, and also identified an 18% increase in food allergies amongst the United States children over the past 10 years. Food-induced anaphylaxis is the most common cause of anaphylaxis treated in hospital emergency departments. At present, the standard of care for food allergy includes strict avoidance of food allergens and ready access to self-injectable epinephrine. The difficulty in avoiding food allergens and the potential for sudden and life-threatening reactions can diminish health-related quality of life for patients and their families. Thus, novel treatment strategies for food allergy are needed.
Although the impact of food allergies is substantial, their prevalence is remarkably low considering the complexities of the mucosal immune system. The gastrointestinal tract, which is the largest immunologic organ in the body, is normally tolerant of exposure to an enormous array of commensal bacteria and ingested proteins. A single epithelial layer divides the rich antigenic milieu of the lumen from the lamina propria, a loose stroma of connective tissue populated by lymphocytes and other immune cells. In this context, dietary antigens interact with unique populations of antigen-presenting cells (APCs), which are believed to actively suppress T cell responses. Thus oral tolerance can be defined as the antigen-specific suppression of cellular or humoral immune responses following previous oral exposure to the antigen. This hyporesponsiveness likely evolved as an analog of self-tolerance to prevent hypersensitivity reactions to food proteins and bacterial antigens present in the commensal flora. Food hypersensitivity can thus be considered a failure in establishing oral tolerance or a breakdown in existing tolerance.
For centuries, tolerance induction has been used as a strategy for preventing allergic reactions. In 1829 Dakin reported that certain populations of Native Americans ate poison ivy leaves to prevent contact hypersensitivity reaction to urushiol. In a classic experiment, Wells later found that guinea pigs repeatedly fed hen's egg protein were protected from anaphylaxis when injected with the protein. Experiments in the mid-twentieth century established that the inhibition of active immune responses following oral feeding of an antigen is T cell-mediated. Age, genetics, route of initial antigen exposure, and the physical properties of allergens have also been shown to impact the development of tolerance. More recently, understanding oral tolerance has been recognized as a key component in developing strategies for preventing and treating food allergies. Data from early-phase clinical trials suggest both sublingual and oral immunotherapy are effective in reducing sensitivity to allergens, but more study is needed to understand if and how tolerance is generated. In this article we discuss the relationship of food allergy and oral tolerance, review the mechanisms of oral tolerance, and discuss important new observations on the roles of antigen-presenting cells in tolerance. The reader is referred to a recent review in this journal and others for information on novel clinical prevention and treatment paradigms for food allergy.