Reviews and feature article
Oral tolerance, food allergy, and immunotherapy: Implications for future treatment

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The lumen of the gastrointestinal tract is exposed daily to an array of dietary proteins. The vast majority of proteins are tolerated through suppression of cellular or humoral responses, a process known as oral tolerance. However, in approximately 6% of children and 4% of adults in the United States, tolerance to a given dietary antigen either is not established or breaks down, resulting in food hypersensitivity. Although food allergies can result in sudden and life-threatening symptoms, their prevalence is remarkably low considering the complexities of the gut-associated mucosal system. Suppression involves signaling by an array of nonprofessional antigen-presenting cells, dendritic cells, and regulatory T cells, as well as lymphocyte anergy or deletion. Several factors, including antigen properties, route of exposure, and genetics and age of the host, contribute to the development of oral tolerance. 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 tolerance has shifted focus of treatment and prevention toward inducing tolerance. Data from early-phase clinical trials suggest both sublingual and oral immunotherapy are effective in reducing sensitivity to allergens. In this article we review the mechanisms of tolerance, discuss aberrations in oral tolerance, and provide information on novel prevention and treatment paradigms for food allergy.

Section snippets

Mechanisms of tolerance

Experiments in the mid-20th century established that oral feeding of an antigen can induce T cell–mediated inhibition of active immune responses.11 Mice that are immunized and boosted subcutaneously with an antigen exhibit strong in vitro cell-mediated and antibody responses to the antigen. In contrast, mice that are first fed the antigen orally and then immunized subcutaneously have greatly reduced in vitro immune responses to the antigen. Transferring T cells from antigen-fed mice to naive

Factors important in tolerance

Several factors, including antigen properties, route of exposure, and genetics and age of the host, contribute to the development of oral tolerance. In general, soluble antigen is more tolerogenic than particulate antigen, yet paradoxically, most food allergens are soluble proteins. Solubility can change during food preparation, and peanut allergens become less soluble with progressive roasting, a process that increases the capacity of peanut-specific IgE binding to the protein.43 The route of

Paradigms for inducing tolerance

Caseins, which account for about 80% of protein in cow's milk, are the major allergens responsible for cow's milk allergy. Cow's milk allergy is a significant problem in young children but is often outgrown within the first 3 to 4 years of life. To better understand the natural history of cow's milk allergy, Chatchatee et al50 identified IgE- and IgG-binding epitopes on 2 different caseins: β-casein and κ-casein. They isolated 9 IgE- and IgG-binding epitopes each on β-casein and 8 IgE- and 4

Conclusions

Understanding tolerance versus hypersensitivity is critical for the treatment of patients who have food allergies and for those who are susceptible to the disease. Further studies are needed to better understand the effectiveness of inducing tolerance to various allergens, the optimal mode of delivering antigen, and whether induction can result in long-term tolerance versus short-term desensitization. SLIT and OIT strategies appear to be effective in inducing short-term desensitization,

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    Disclosure of potential conflict of interest: A. W. Burks has consulting arrangements with Novartis, McNeil Nutritionals, and Mead Johnson; owns stock in Allertein and Mast Cell; has received research support from the National Institutes of Health, the Food Allergy and Anaphylaxis Network, Gerber, and Mead Johnson; is on the speakers' bureau for EpiPen/Dey; is on the advisory board for Dannon; and has served as a member for Genentech and Nutricia. S. Laubach has received research support from the National Institutes of Health. S. M. Jones has consulting arrangements with the Food Allergy and Anaphylaxis Network and has received research support from the National Institutes of Health, the Food Allergy and Anaphylaxis Network, the National Peanut Board, Mead Johnson, and DYAX Corporation.

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