ReviewOral immunotherapy for food allergy
Introduction
Food allergy affects 8% of children and 5% of adults in the U.S. [1], [2], and epidemiological data generally indicate an increase in its prevalence [2]. However, the current standard of care for all food allergies is minimal, consisting of food-allergen avoidance and emergency treatment of potentially fatal allergen-induced systemic reactions with injectable epinephrine; the constant risk of severe allergic reaction adversely impacts the quality of life of food-allergy patients and their families. The growing, global, unmet need for safe and effective treatment can best be met by understanding the cellular and molecular mechanisms of promising immunotherapeutic approaches under clinical investigation [3].
The mechanistic role of IgE in atopic immune responses provides a useful distinction among types of food allergy: IgE-mediated food allergy is characterized by acute, potentially life-threatening immune responses, while non-IgE-mediated food allergy is driven by slower, cell-mediated responses. This review focuses on IgE-mediated food allergy, in which food allergen epitopes bind to IgE molecules which also bind FcεRI receptors on immune effector cells, such as basophils, mast cells, and antigen-presenting dendritic cells. Epitope-specific crosslinking of the IgE-bound receptors results in degranulation of basophils and mast cells, releasing pre-formed histamine and other inflammatory molecules that generate a rapid atopic reaction [4]. Additional inflammatory mediators, such as platelet activating factor, leukotrienes and the cytokines interleukin-4 (IL-4), IL-5, and IL-13, are then produced de novo, augmenting the inflammatory immune response [4]. Membrane-bound IgE on B cells also forms a complex with CD23 and CD21, increasing production of soluble IgE [5] and escalating the IgE-mediated immune response. The resulting symptoms may include gastrointestinal responses (e.g., pruritus, abdominal pain, nausea, vomiting), respiratory responses (e.g., airway inflammation, wheezing), dermal responses (e.g., pruritus, angioedema, urticaria), and systemic responses (e.g., hypotension, hypothermia). An anaphylactic response involves multiple organ systems and rapidly may become life-threatening [6].
Recent clinical studies reviewed here provide evidence that oral immunotherapy (OIT) can be used safely and effectively to reduce the sensitivity of food allergy (FA) patients to food antigens (Ag). However, it is not yet clear the extent to which such patients develop desensitization (DS, defined as a lack of clinical reactivity to Ag, the maintenance of which requires regular Ag exposure), as distinct from sustained unresponsiveness (SU), in which the patient exhibits a long-term and perhaps permanent loss of reactivity to Ag that is independent of continued Ag exposure. Novel findings from our group and others are elucidating the mechanisms by which DS and SU are established through OIT.
In OIT, FA study participants ingest small but gradually increasing doses of specific food Ag over the course of several months, with the goal of progressively retraining their immune responses to establish DS and possibly SU to the Ag (Fig. 1) [7]. Because other FA diagnostic tools, such as measurements of blood levels of Ag-specific IgE and skin-prick tests, are known to generate false positives that could confound research results [8], [9], an initial, definitive FA diagnosis is made using a double-blind, placebo-controlled, oral food challenge (DBPCFC) with one or more target Ag. On the first day of OIT, the participant ingests increasing doses of the target Ag under clinical care to determine the highest tolerated dose. After this initial-day dose escalation, the highest tolerated dose is used to begin a dose-escalation phase, in which the dose is increased in a visit to the clinic every 1–2 weeks until the designated maintenance dose is tolerated. Then, during the maintenance phase which ranges from months to years, the participant daily ingests the maintenance dose of the FA. A desensitization DBPCFC is administered in the clinic at the end of the maintenance phase, to assess the efficacy of the treatment protocol. If a statistically significant increase in the tolerated dose to a level that is protective against accidental Ag exposure is found, the OIT is deemed successful. DS, or a reduction in adverse immune response that is maintained through regular Ag exposure, is often achieved through OIT, along with lower risk of anaphylaxis and increased quality of life for FA participants and their families.
To test for SU, an Ag avoidance phase of weeks to months may be added after the termination of OIT, ending with a followup DBPCFC. If the target dose is tolerated after the avoidance phase, the participant has achieved SU to that dose, a reduced immune response to Ag that persists even without continued, regular Ag exposure. Since a DBPCFC is not prospective, the duration and variance of SU are unknown. The mechanisms underlying SU, its potential durability and defeat, and its comparison to healthy tolerance are promising research areas that could be of tremendous benefit to our understanding of healthy, atopic, and therapy-induced immune states.
The field of FA OIT is very active and growing. This review focuses on recent, peer-reviewed studies, prioritizing phase II trials with a placebo arm, clearly defined dosing, and those that required a screening DBPCFC (sDBPCFC) to avoid confounding due to false positive FA diagnoses. We also prioritize studies with associated, long-term followup to assess SU, and associated mechanistic studies. We highlight recent advances in the safety, efficacy, and mechanistic understanding of OIT.
Section snippets
Immune mechanisms
The immunological mechanisms of: (1) the establishment and maintenance of a healthy state of immune tolerance to food antigens; (2) food allergy; and (3) desensitization established through OIT are drawing increasing research interest. The evolution of this research is addressed in several recent reviews [10], [11], [12], [13], [14], [15], [16]; key features are outlined here. While we focus on food allergy research in humans, we also cite relevant hypotheses based on research in closely
OIT
OIT trials are very valuable resources for the study of the cellular and molecular mechanisms by which FA pathology and treatment are effected. For example, a pilot study to examine the role of invariant natural killer T cells (iNKT) in OIT was performed with 11 highly allergic children having a history of anaphylaxis to cow’s milk and a positive sDBPCFC [68]. An open course of lactose-free cow’s milk OIT was given, with antihistamine and with a protocol for temporary dose reduction during
Further mechanistic insights
Mechanistic studies of different immune cell subsets during short- and long-term courses of OIT are important to perform, to try to discover new targets for rational drug design in food allergy in the future. For example, a study was recently published using peripheral blood mononuclear cells (PBMCs) from 21 peanut-allergic (PA) individuals and 7 healthy controls to determine whether functional peanut-specific type 1 regulatory T cells (Tr1), which are potent immune response suppressors, could
Conclusion
As oral immunotherapy advances the management and prevention of food allergy, research aimed at its molecular and cellular mechanisms advances our understanding of healthy, pathological, and therapeutic human immune responses. Innovations to extend the safety and efficacy of OIT prominently include the use of blocking antibodies as adjuvants to OIT, interfering with various effector pathways that otherwise could bring about the clinical manifestations of IgE-mediated atopic immune response.
Acknowledgements
The authors would like to thank Vanitha Sampath for creating Fig. 2, Fig. 3, Fig. 4 and the bibliography. This work was supported by NIH grant U19AI104209, the Bezos Family Foundation, the FARE Center of Excellence, the Myra Reinhard Foundation, and the Sean N. Parker Center for Allergy and Asthma Research at Stanford University.
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