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Future Approaches to

Anna Nowak-Wegrzyn, MD

ABSTRACT. affects ϳ2% of the general the family of a food-allergic child. Therefore, accu- US population, and its prevalence seems to be increasing. rate diagnosis of food allergy is of utmost impor- Despite the potential for a fatal outcome, no definitive tance and currently relies on oral food challenges, therapies are available for food allergy. This article re- which are not without substantial risks. Considering views novel approaches for the diagnosis and treatment the severity of food allergy as well as its increasing of food allergy. Improved diagnostic methods include prevalence, improved diagnostic tests and definitive more precise in vitro and in vivo tests for immunoglob- ulin E-mediated food , in vitro assays for pre- therapies are desirable. This article reviews the re- dicting development of oral tolerance, and novel nonin- cent developments in the diagnosis and potential vasive tests for cell-mediated food allergies such as patch treatments for food allergy. testing, assays, and detection of ac- tivation markers. Several promising novel immuno- NOVEL APPROACHES TO THE DIAGNOSIS OF modulatory approaches to food allergy are discussed, FOOD ALLERGY including monoclonal anti-; probiot- Food-allergic disorders can be classified according ics; traditional Chinese medicine; and to the pathophysiological role of immunoglobulin E with modified food , peptides, bacterial adju- vants, and immunostimulatory sequences. Pediatrics (IgE) : immediate; IgE-mediated food al- 2003;111:1672–1680; food allergy, diagnosis, immuno- lergy (eg, ); mixed mechanisms, modulatory therapy, , anti-IgE antibodies, im- involving both IgE- and cell-mediated reactions (eg, munotherapy, traditional Chinese medicine, patch testing. atopic , allergic eosinophilic gastroenteri- tis); and delayed onset, cell-mediated food allergy (eg, food -induced enterocolitis syndrome). ABBREVIATIONS. IgE, immunoglobulin E; IL, ; IFN-␥, ␥-interferon; TNF, tumor necrosis factor; TGF-␤, tumor growth Currently available diagnostic tests detect food-spe- factor-␤; TCM, traditional Chinese medicine; FAHF-1, food allergy cific IgE, either in the skin (prick skin test) or in the herbal formula-1; HKL, heat-killed ; ISS-ODN, oligode- systemic circulation (serum IgE levels), but there are oxynucleotide immunostimulatory sequences. no standard tests for the diagnosis of non–IgE-medi- ated food allergies. New approaches to the diagnosis ood allergy affects ϳ2% of the general US pop- of food allergy are aimed toward 3 areas: better ulation, and its prevalence seems to be increas- characterization of the clinical correlation of - ing in concert with the increasing prevalence of specific IgE levels and prick skin tests, improved in F 1,2 vitro assays for predicting the development of clini- the extrinsic and environmental allergies. However, unlike other allergic diseases, food allergy cal tolerance in IgE-mediated food allergy, and the is the only disorder for which there is no specific creation of in vivo and in vitro techniques for eval- therapy, which is particularly troubling considering uating cell-mediated food allergies (Table 1). the potential for severe reactions. In fact, food-in- duced anaphylaxis is the single most common cause Improved Interpretation of Food-Specific IgE Levels of anaphylaxis evaluated in emergency departments Double-blind, placebo-controlled food challenges in the United States and the United Kingdom.3,4 Di- are the gold standard for diagnosis of food allergy; etary avoidance is the current standard of care, but however, they are labor-intensive and carry risks accidental ingestions of food are common to the patient. A number of studies have correlated because of the ubiquitous presence of certain , serum food-specific IgE levels (measured such as peanut, soy, , and egg, and compounded by CAP-System Fluorescent Immunoassay; by poor labeling practices and cross-contamination Pharmacia-Upjohn Diagnostics, Uppsala, Sweden) to during processing. Furthermore, in cases of multiple oral food challenge outcomes. Diagnostic decision food allergies, restricted diets may result in unbal- points of 95% or greater positive predictive value for anced and pose a considerable hardship to clinical reactivity to milk (15 kUA/L), egg (7 kUA/L), peanut (14 kUA/L), and fish (20 kUA/L) were estab- lished in a recent prospective study by Sampson,5 in From the Elliot and Roslyn Jaffe Food Allergy Institute, Division of Allergy and Immunology, Department of Pediatrics, Mount Sinai School of Medi- which 100 children (median age: 3.8 years) were cine, New York, New York. evaluated. Food-specific IgE levels exceeding the Received for publication Sep 11, 2002; accepted Oct 30, 2002. “diagnostic decision point values” indicate that the Reprint requests to (A.N.-W.) Division of Allergy/Immunology, Mount patient is Ͼ95% likely to experience an allergic reac- Sinai School of Medicine, Box 1198, One Gustave L. Levy Place, New York, NY 10029-6574. E-mail: [email protected] tion after the ingestion of the specific food, therefore PEDIATRICS (ISSN 0031 4005). Copyright © 2003 by the American Acad- eliminating the need to perform the oral food chal- emy of Pediatrics. lenge. Detectable food-specific IgE levels that are

1672 PEDIATRICS Vol.Downloaded 111 No. 6 from June www.aappublications.org/news 2003 by guest on September 23, 2021 TABLE 1. Novel Approaches to Diagnosis of Food Allergy IgE Mixed Non-IgE Anaphylaxis Atopic dermatits FPIES Urticaria Allergic eosinophilic Allergic enteropathy gastroenteritis Food-specific serum IgE levels Patch testing Prick skin tests Peripheral T- proliferation assays In vitro tests for predicting oral tolerance Cytokine release upon food stimulation Recombinant allergens Inflammatory (IL-4, TNF-␣) in serum and stool Markers of eosinophil activation in stool (ECP) ECP indicates eosinophilic cationic protein. lower than the diagnostic decision point value but of milk-allergic children become clinically tolerant to Ͼ 8 0.35 kUA/L (lower limit of detection of the CAP milk by 4 years of age. Currently available diagnos- immunoassay) represent a decreasing risk with de- tic methods for food allergy, such as prick skin tests creasing levels of food-specific IgE. Their clinical sig- and serum food allergen-specific IgE levels, do not nificance requires ultimate determination by an oral distinguish between children who will achieve food food challenge. Several studies observed that in in- tolerance and those who will have persistent food fants and young children, lower food-specific IgE allergy. Previous studies aimed at the identification levels were associated with positive food challenge of markers for tolerance showed that children with outcomes, suggesting that lower IgE levels have long-lasting , compared with those who greater positive predictive value under the age of 2 outgrew the allergy, have higher levels of milk-spe- years. For , a level of 2 kUA/L or above in cific IgE and higher specific IgE to milk proteins children younger than 2 years had 95% positive pre- including casein- and ␤-lactoglobulin.9,10 dictive value, whereas for milk, a level of 5 kUA/L in IgE binding sites (epitopes) on the allergenic pro- infants younger than 1 year had 95% positive predic- tein may consist of segments of consecutive amino tive value.6,7 acids (so-called sequential epitopes) or amino acids from different parts of the protein sequence, brought In Vitro Assays for Predicting the Development of together by protein folding (nonsequential epitopes; Clinical Tolerance in IgE-Mediated Food Allergy Fig 1). A study by Cook and Sampson11 suggested The majority of children outgrow allergies to foods that egg-allergic children who developed significant such as milk, egg, soy, and ; in fact 75% to 80% amounts of IgE antibodies to “sequential” epitopes

TABLE 2. Immunomodulatory Therapies for Food Allergy Therapy Mechanism of Action Effects Comments Monoclonal anti-IgE Binds to circulating IgE and Improves symptoms of asthma Subcutaneous at monthly intervals, prevents IgE deposition on and allergic , possible unknown long-term mast cells (“disarms” mast protection against food consequences of IgE elimination cells) anaphylaxis Probiotics Possibly increased IgA, IL-10, Improves severity of atopic Oral dietary supplement, generally suppression of TNF-␣, and dermatitis in infants with milk safe and well-tolerated inhibition of T-cell activation allergy, prevents development of in at-risk infants TCM Downregulation of Th2 cytokines Reverses allergic inflammation Oral, generally safe and well (IL-4, IL-5), upregulation of in the airways, protects mice tolerated Th1 cytokines (IFN-␥, IL-12), from peanut anaphylaxis decreased allergen-IgE Conventional peanut Altered T-cell responses, Increased oral peanut tolerance Subcutaneous injections of immunotherapy upregulation of suppressor gradually increasing doses of cells allergen, unacceptably high rate of serious adverse events Modified peanut Binding to mast cells eliminated, Protection against peanut Improved safety profile compared immunotherapy altered T-cell responses anaphylaxis in mice with conventional immunotherapy, requires identification of IgE binding sites Peptide Binding to mast cells eliminated, Protection against peanut Improved safety profile compared immunotherapy altered T-cell responses anaphylaxis in mice with conventional immunotherapy, does not require identification of IgE- binding epitopes Heat-killed bacteria Potentiation of Th1 responses Protection against peanut Concern for toxicity of bacterial mixed with or anaphylaxis in mice adjuvants, excessive Th1 expressing modified stimulation, and potential for peanut proteins Immunostimulatory Potent stimulation of Th1 via Protection against peanut Not shown to reverse established sequences (ISS- activation of antigen- sensitization in mice , concern for ODN) presenting cells, natural killer excessive Th1 stimulation, and cells, and B cells; increased potential for autoimmunity Th1 cytokines

Downloaded from www.aappublications.org/news by guest on September 23, 2021 SUPPLEMENT 1673 Fig 1. Sequential and nonsequential allergen epitopes. of ovomucoid (major allergen in egg) were more higher risk for severe systemic reactions among the likely to have persistent egg allergy, whereas the patients whose symptoms are likely to remain con- children who developed predominantly IgE to “non- fined to the oropharyngeal mucous membranes (pol- sequential” epitopes were more likely to outgrow len-food allergy syndrome or oral allergy syn- their egg (Fig 1). Subsequent studies drome).18,19 confirmed that ϳ50% of children who reacted to freeze-dried (conformational nonsequen- DIAGNOSIS OF NON–IgE-MEDIATED FOOD tial epitopes preserved) tolerated cooked egg white ALLERGY (conformational nonsequential epitopes destroyed A growing body of evidence supports the crucial by high temperature).12 It was recently demonstrated role of T in the pathophysiology of that children with persistent IgE-mediated milk al- non–IgE-mediated food allergy. As the majority of lergy have higher levels of IgE to sequential epitopes the non–IgE-mediated food-allergic disorders affect from ␣s1, ␣s2, and ␬-casein and that specific IgE the gastrointestinal tract, and are binding to particular sequential epitopes in ␣s1-ca- the requisite diagnostic tools for the detection of sein may be a predictive factor for persistence of cow inflammatory cells or their products. For obvious milk allergy.13,14 These observations suggest that reasons, noninvasive diagnostic methods are desired perhaps differential epitope recognition is a general to assist in a tedious process of identifying the of- feature of food allergy and additional studies should fending foods through elimination diets and chal- elucidate the diagnostic utility of tests that detect lenge procedures. Novel approaches to non–IgE-me- binding to conformational and sequential epitopes. diated food allergy include food allergy patch testing, measurement of cytokine production by T Recombinant Allergens lymphocytes after stimulation with food allergen, Many allergenic proteins have been identified, se- and measurement of cytokines and eosinophil mark- quenced, and cloned. The recombinant allergens are ers in the stool. It should be noted that none of these being investigated currently for their applicability in diagnostic methods has been evaluated rigorously, the diagnosis of allergic diseases.15 Recombinant al- and their clinical applicability remains to be deter- lergens of high purity offer superior safety and spec- mined in future studies. ificity in allergy testing, although diagnostic sensitiv- ity is generally lower than that of natural allergen Patch Testing extracts.16,17 Recombinant allergens may be of special Patch testing is typically used for diagnosis of value in diagnosing allergy to plant foods in subjects delayed contact hypersensitivity reactions in which T with allergy to pollens. For instance, pure recombi- cells play a prominent role. Patch testing involves nant transfer proteins could identify patients at prolonged contact of the allergenic extract with intact

1674 SUPPLEMENT Downloaded from www.aappublications.org/news by guest on September 23, 2021 skin under occlusion for 48 hours. The results are cause they primarily reflect exposure to the food in evaluated 20 minutes after removing the patch and the .25 However, the profile of cytokines pro- again at 72 hours for final evaluation. Positive reac- duced by lymphocytes has been shown to differ in tions to patch tests consist of erythema and indura- food-allergic children, producing more Th2-type cy- tion. Patch testing for the diagnosis of food allergy in tokines (eg, interleukin [IL]-4), compared with non- children with and allergic eosino- allergic children, producing predominantly Th1-cy- philic esophagitis has been investigated in a number tokines (eg, ␥-interferon [IFN-␥]), after exposure to of studies.20–24 In young children with challenge- food allergens.26 In milk-allergic children with gas- proven milk allergy, prick skin tests were positive in trointestinal symptoms, peripheral blood lympho- 67% of the cases with -onset reactions (under 2 cytes were shown to produce significantly more tu- hours) to milk challenge, whereas patch tests tended mor necrosis factor (TNF)-␣ on stimulation with milk to be negative. Patch tests were positive in 89% of than in nonallergic children.27 As children with food children with delayed-onset reactions (25–44 hours), allergy and atopic dermatitis frequently have chronic although prick skin tests were frequently negative.20 allergic inflammation in their gastrointestinal tract, it In another study of children with atopic dermatitis, was hypothesized that acute-phase proteins, proin- the combination of a positive with evi- flammatory cytokines, or eosinophil secretory pro- dence of specific IgE or with positive prick skin test teins in the stool might be increased and reflect the had the highest positive predictive value.21 These severity of the intestinal inflammation. Indeed, in results indicate that the combination of patch testing some studies, increased amounts of fecal ␣1-antit- and detection of IgE could enhance the accuracy of rypsin, TNF-␣, and eosinophil cationic protein were diagnosing food allergy and may eliminate the need recovered in children with atopic dermatitis and for oral food challenges. However, at this time, atopy food allergy compared with children without atopic patch testing remains an investigational method. Be- dermatitis.28,29 These findings suggest that such non- fore incorporating atopy patch testing into clinical invasive tests may be of value in monitoring the practice, standardization of the reagents, timing of severity of intestinal inflammation in children with reading results, and scoring system for the interpre- food allergy; however, more studies are necessary to tation of the results is necessary. establish the usefulness of this approach.

In Vitro Assays for Lymphocyte and Eosinophil IMMUNOMODULATORY THERAPIES FOR FOOD Activation ALLERGY The in vitro tests for lymphocyte and eosinophil As first noted in murine studies, the Th1/Th2 par- activation have been investigated in a number of adigm is applied to human allergic diseases. It pos- studies. In general, lymphocyte proliferation assays tulates that the type of immune response generated have been proved not to be helpful in distinguishing to an antigen depends on the profile of cytokines between children with and without food allergy be- released by CD4ϩ T-helper cells (Fig 2). Typical Th1

Fig 2. Food allergy immunomodulatory therapies.

Downloaded from www.aappublications.org/news by guest on September 23, 2021 SUPPLEMENT 1675 cytokines are IFN-␥ and tumor necrosis factor-␤ investigational therapies for food allergy in vivo be- (TNF-␤), whereas Th2 cytokines include IL-4, IL-5, came possible when well-characterized mouse mod- and IL-13. In addition, regulatory cytokines such as els of peanut and cow milk anaphylaxis were estab- IL-12, IL-10, and TGF-␤ are of paramount impor- lished (Fig 3).32,33 tance in maintaining the state of dynamic balance between Th1 and Th2 responses. Allergic diseases Humanized Monoclonal Anti-IgE are characterized by relative predominance of Th2- Allergen-specific IgE antibodies play a central role type responses to innocuous allergens. Most of the in the pathophysiology of atopic disorders, including immunomodulatory therapeutic approaches to food food allergy, and are an excellent target to interrupt allergy operate on the premise of restoring the Th1/ the allergic process. IgE antibodies bind to high- Th2 balance or activating regulatory T lymphocytes affinity receptors (Fc⑀RI) on the surface of mast cells (Fig 2). and . Cross-linking of IgE molecules on the In conventional for aller- surface of mast cells by allergen leads to the release gic rhinitis and asthma, gradually increasing doses of of preformed mast-cell mediators (early phase of allergen are injected subcutaneously. This results in allergic reaction) as well as synthesis of proinflam- decreased symptoms attributable to a variety of im- matory cytokines and chemokines that result in a munologic alterations, including a decline in aller- late-phase reaction (Fig 4).34 Humanized monoclonal gen-specific IgE levels, an increase in allergen-spe- anti-IgE antibodies have been engineered to disrupt cific IgG4 antibodies, decreased this process. They bind to the constant region (third release, decreased lymphocyte proliferation, genera- domain of the Fc region) of IgE molecules, the point tion of allergen-specific suppressor T cells, increased at which IgE binds to the Fc⑀R. This prevents IgE production of IFN-␥, and decreased production of from binding to both high- (Fc⑀RI) and low-affinity Th2 cytokines such as IL-4 and TNF-␣.30 Conven- (Fc⑀RII) IgE receptors. With the decrease in available tional subcutaneous allergen immunotherapy has IgE antibody molecules, anti-IgE leads to a down- been attempted for peanut allergy. In a double-blind, regulation of Fc⑀RI expression on mast cells placebo-controlled trial of rush (rapidly increasing and basophils and to decreased histamine release.35 doses) peanut immunotherapy, increased tolerance In clinical trials of anti-IgE for the treatment of to oral feeding with peanut was observed in 4 of 6 asthma and , symptomatic improve- patients who received the active immunotherapy but ment was observed when circulating levels of IgE in none of the 6 control patients. However, the rate of antibodies were significantly reduced.36,37 A multi- serious adverse reactions was unacceptably high, center, randomized, double-blind, placebo-con- even during the maintenance phase of immunother- trolled clinical trial recently evaluated humanized apy (39%).31 This important clinical study suggested monoclonal anti-IgE antibody in the treatment of that immunomodulation could be used successfully peanut anaphylaxis. Patients with peanut allergy to induce oral tolerance in food-allergic subjects if were orally challenged with peanut protein (double- activation of mast cells by allergen were eliminated blind, placebo-controlled food challenge) at the entry and safety were improved. and after 4 monthly subcutaneous injections of anti- Better characterization of allergen processing, pre- IgE or placebo to determine the amount of peanut sentation, and binding led to development of new protein required to induce anaphylaxis. Preliminary immunomodulatory approaches to food allergy. In reports indicate that anti-IgE therapy significantly addition, characterization and cloning of major pea- increased the amount of peanut protein necessary to allergens (Ara h1, Ara h2, and Ara h3) has made induce allergic symptoms. If confirmed, then anti- recombinant protein- and DNA-based peanut aller- IgE may be used to treat patients with any IgE- gen gene therapy possible. Finally, testing of the mediated food allergy, although the protection

Fig 3. Mouse model of peanut anaphylaxis.

1676 SUPPLEMENT Downloaded from www.aappublications.org/news by guest on September 23, 2021 Fig 4. Mechanism of anti-IgE therapy. against anaphylaxis would require continued ther- peanut proteins (Ara h1, Ara h2, and Ara h3) were apy at regular time intervals indefinitely. isolated and purified; IgE-binding and T-cell epitopes were mapped; and the DNA encoding these Traditional Chinese Medicine proteins was isolated, sequenced, and cloned.43 En- Traditional Chinese medicine (TCM) has been gineered DNA encodes proteins that differ by a sin- used successfully in Asia for centuries for treatment gle amino acid within each of IgE-binding epitopes of diverse diseases, including asthma and environ- (Fig 5A). The engineered recombinant proteins bind mental allergies. TCM, based on herbal remedies, is little IgE antibodies from peanut-allergic patients but generating increased interest because of its reported promote T-cell proliferation that is comparable to effectiveness, favorable safety profile, and low native peanut proteins. In vivo efficacy of the engi- cost.38,39 Despite extensive clinical experience with neered recombinant proteins was tested in the mu- TCM in Asia, the mechanism of action is largely rine model of peanut anaphylaxis. Mice were sensi- unknown and TCM has not been studied rigorously tized to whole peanut and then desensitized by both in randomized clinical trials. Li et al40 investigated subcutaneous and intranasal administration of mod- the effect of TCM in a murine model of allergic ified Ara h2 (3 doses a week for 4 weeks). Desensi- asthma and showed reversal of allergic airway hy- tization with the modified Ara h2 protein suppressed perreactivity. Recently, the same group used a mix- synthesis of Ara h2-IgE and resulted in significantly ture of several herbs, designated food allergy herbal decreased symptoms on oral peanut challenge com- formula-1 (FAHF-1), for the treatment of peanut al- pared with a control group treated with native Ara lergy in mice. FAHF-1 significantly reduced mast- h2.44,45 cell and histamine release and com- Bacterial adjuvants are being used to increase effi- pletely prevented peanut anaphylaxis. FAHF-1 cacy of modified peanut vaccines. Bacteria are potent decreased peanut-IgE levels; peanut-induced lym- stimulants of Th1 immune responses and increase phocyte proliferation; and IL-4, IL-5, and IL-13 pro- IFN-␥ production. Heat-killed Listeria (HKL) has duction, whereas it did not affect IFN-␥ synthesis. been shown to reverse established allergic airway Importantly, FAHF-1 was well tolerated and had no hyperreactivity in mice.46 In a dog model, a single apparent toxic effects on kidney or liver function.41 subcutaneous treatment with a mixture of HKL, milk, and wheat significantly reduced immediate Mutated Allergen Protein Immunotherapy skin test reactions and prevented anaphylactic symp- The major safety concern regarding food allergen toms after oral food challenge.47 Li et al48 recently immunotherapy has been addressed by engineering tested the efficacy of a mixture of HKL and modified “hypoallergenic” forms of major allergenic food pro- peanut proteins (Ara h1, Ara h2, and Ara h3) in a teins. These mutated (“engineered”) major food pro- murine model of peanut anaphylaxis. Immunother- teins have lost their ability to bind to IgE but retained apy was initiated 10 weeks after sensitization (once a the ability to interact with T cells.42 The 3 major week for 3 weeks) and was shown to reduce peanut-

Downloaded from www.aappublications.org/news by guest on September 23, 2021 SUPPLEMENT 1677 Fig 5. Modified recombinant allergens and peptide immunotherapy. A, Modified recombinant allergen. The substitution of a single amino acid within the IgE-binding epitope results in abrogation of IgE binding. B, Peptide immunotherapy. The sequence of a protein is represented by the overlapping peptides (10–20 amino acids long) that provide all possible T-cell epitopes, but binding to IgE antibody is eliminated. specific IgE synthesis as well as anaphylactic re- prevent anaphylactic reactions in peanut-sensitized sponses to oral peanut challenge. Heat-killed Esche- mice. More extensive desensitization protocols are richia coli expressing modified peanut proteins is being investigated. being investigated in the same model. Although lower doses for desensitization were required using Immunostimulatory Sequences HKL and Heat-killed E coli, the safety of these ther- Certain portions of bacterial DNA designated as apeutic approaches need additional evaluation. oligodeoxynucleotide immunostimulatory se- quences (ISS-ODN) are potent stimulators of Th1 Peptide Immunotherapy responses. These bacterial DNA components activate The effect of eliminating IgE binding can also be antigen-presenting cells, natural killer cells, and B achieved with vaccines that consist of overlapping cells and upregulate Th1 cytokine production (eg, peptides (10–20 amino acids long) that represent the IFN-␥). ISS-ODNs have been shown to prevent air- entire sequence of a specific protein (Fig 5B).44 The way allergic inflammation in the murine models of antigen-presenting cells are provided with all possi- asthma.50 Li and colleagues51 studied the prophylac- ble T-cell epitopes, but mast cells are not activated tic use of ISS-conjugated peanut protein Ara h2 in because the short peptides are of insufficient length mice later sensitized with peanut allergen. Mice were to cross-link 2 IgE molecules. Peptide immunother- immunized intradermally with ISS-conjugated Ara apy allows for formulation of vaccines against any h2 or control ISS. Four weeks later, mice were orally food in which major allergenic proteins are known sensitized with peanut and challenged with Ara h2 5 because IgE binding sites for each food protein do weeks later. Mice that were immunized with ISS-Ara not have to be mapped, allergen-specific DNA does h2 conjugate did not develop severe anaphylactic not need to be mutated, and engineered recombinant symptoms after peanut challenge, and their postchal- proteins are not required. Major peanut protein Ara lenge plasma histamine levels were significantly h2 peptide mixture is currently being evaluated in a lower than in sham-treated mice, which developed mouse model of peanut allergy.49 Pretreatment with anaphylactic symptoms. These data suggest that an- 2 doses of the major peanut protein Ara h2 peptide tigen ISS-ODN immunotherapy may prevent the de- mixture before peanut challenge has been shown to velopment of food allergy; however, its potential to

1678 SUPPLEMENT Downloaded from www.aappublications.org/news by guest on September 23, 2021 reverse established food allergy remains to be deter- bring real hope to the patients for whom no specific mined. therapy is currently available.

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