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Future therapies for food allergies

2011; Elsevier BV; Volume: 127; Issue: 3 Linguagem: Inglês

10.1016/j.jaci.2010.12.1098

1097-6825

Anna Nowak‐Węgrzyn, Hugh A. Sampson,

Eosinophilic Esophagitis

Food allergy is an increasingly prevalent problem in westernized countries, and there is an unmet medical need for an effective form of therapy. A number of therapeutic strategies are under investigation targeting foods that most frequently provoke severe IgE-mediated anaphylactic reactions (peanut, tree nuts, and shellfish) or are most common in children, such as cow's milk and hen's egg. Approaches being pursued are both food allergen specific and nonspecific. Allergen-specific approaches include oral, sublingual, and epicutaneous immunotherapy (desensitization) with native food allergens and mutated recombinant proteins, which have decreased IgE-binding activity, coadministered within heat-killed Escherichia coli to generate maximum immune response. Diets containing extensively heated (baked) milk and egg represent an alternative approach to food oral immunotherapy and are already changing the paradigm of strict dietary avoidance for patients with food allergy. Nonspecific approaches include monoclonal anti-IgE antibodies, which might increase the threshold dose for food allergen in patients with food allergy, and a Chinese herbal formulation, which prevented peanut-induced anaphylaxis in a murine model and is currently being investigated in clinical trials. The variety of strategies for treating food allergy increases the likelihood of success and gives hope that accomplishing an effective therapy for food allergy is within reach. Food allergy is an increasingly prevalent problem in westernized countries, and there is an unmet medical need for an effective form of therapy. A number of therapeutic strategies are under investigation targeting foods that most frequently provoke severe IgE-mediated anaphylactic reactions (peanut, tree nuts, and shellfish) or are most common in children, such as cow's milk and hen's egg. Approaches being pursued are both food allergen specific and nonspecific. Allergen-specific approaches include oral, sublingual, and epicutaneous immunotherapy (desensitization) with native food allergens and mutated recombinant proteins, which have decreased IgE-binding activity, coadministered within heat-killed Escherichia coli to generate maximum immune response. Diets containing extensively heated (baked) milk and egg represent an alternative approach to food oral immunotherapy and are already changing the paradigm of strict dietary avoidance for patients with food allergy. Nonspecific approaches include monoclonal anti-IgE antibodies, which might increase the threshold dose for food allergen in patients with food allergy, and a Chinese herbal formulation, which prevented peanut-induced anaphylaxis in a murine model and is currently being investigated in clinical trials. The variety of strategies for treating food allergy increases the likelihood of success and gives hope that accomplishing an effective therapy for food allergy is within reach. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: March 2011. Credit may be obtained for these courses until February 28, 2013.Copyright Statement: Copyright © 2011-2013. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Anna Nowak-Węgrzyn, MD, and Hugh A. Sampson, MDActivity Objectives1.To summarize the current management and candidate therapies for IgE-mediated forms of food allergy.2.To understand that allergen-specific immunotherapy can include feeding patients heat-treated allergen, as well as oral, sublingual, and epicutaneous immunotherapy.3.To recognize that allergen-nonspecific therapy might include humanized monoclonal anti-IgE antibodies, Food Allergy Herbal Formula (FAHF) 1, probiotics, and Toll-like receptor agonists.4.To review key clinical trials and studies in food allergy treatment.Recognition of Commercial Support: This CME activity has not received external commercial support.Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: A. Nowak-Węgrzyn has declared that she has no conflict of interest. H. A. Sampson is a consultant for Allertein Therapeutics, LLC; has received research support from and is a consultant and scientific advisor for the Food Allergy Initiative and the National Institute of Allergy and Infectious Diseases/National Institutes of Health; is a medical advisor for the Food Allergy & Anaphylaxis Network; is a scientific advisor for the University of Nebraska FARRP; and is a 45% owner of Herbal Springs, LLC.Over the past 2 decades, food allergy has emerged as a major public health problem in westernized societies.1Sicherer S.H. Sampson H.A. Food allergy: recent advances in pathophysiology and treatment.Annu Rev Med. 2009; 60: 261-277Crossref PubMed Scopus (208) Google Scholar, 2Sicherer S.H. Epidemiology of food allergy.J Allergy Clin Immunol. 2011; 127: 594-602Abstract Full Text Full Text PDF PubMed Scopus (542) Google Scholar In American children younger than 18 years, the prevalence of food allergy has increased by 18% and the prevalence of peanut allergy has tripled (0.4% to 1.4%) from 1997 to 2008.3Branum A.M. Lukacs S.L. Food allergy among children in the United States.Pediatrics. 2009; 124: 1549-1555Crossref PubMed Scopus (563) Google Scholar, 4Sicherer S.H. Munoz-Furlong A. Godbold J.H. Sampson H.A. US prevalence of self-reported peanut, tree nut, and sesame allergy: 11-year follow-up.J Allergy Clin Immunol. 2010; 125: 1322-1326Abstract Full Text Full Text PDF PubMed Scopus (736) Google Scholar Food allergy is the most common cause of anaphylaxis evaluated in the emergency department in all age groups, and the number of hospitalizations for food-induced anaphylaxis has increased more than 3-fold in the past decade in the United States and United Kingdom.3Branum A.M. Lukacs S.L. Food allergy among children in the United States.Pediatrics. 2009; 124: 1549-1555Crossref PubMed Scopus (563) Google Scholar, 5Gupta R. Sheikh A. Strachan D.P. Anderson H.R. Time trends in allergic disorders in the UK.Thorax. 2007; 62: 91-96Crossref PubMed Scopus (393) Google Scholar, 6Decker W.W. Campbell R.L. Manivannan V. et al.The etiology and incidence of anaphylaxis in Rochester, Minnesota: a report from the Rochester Epidemiology Project.J Allergy Clin Immunol. 2008; 122: 1161-1165Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar Food-induced anaphylaxis occasionally results in fatalities, with more than 90% of deaths in the United States caused by reactions to peanut or tree nuts.7Bock S.A. Munoz-Furlong A. Sampson H.A. Fatalities due to anaphylactic reactions to foods.J Allergy Clin Immunol. 2001; 107: 191-193Abstract Full Text PDF PubMed Scopus (1359) Google Scholar, 8Bock S.A. Munoz-Furlong A. Sampson H.A. Further fatalities caused by anaphylactic reactions to food, 2001-2006.J Allergy Clin Immunol. 2007; 119: 1016-1018Abstract Full Text Full Text PDF PubMed Scopus (772) Google ScholarThe current management of food allergy is limited to strict dietary avoidance, nutritional counseling, and emergency treatment of adverse reactions.9Boyce J. Assa'ad A.H. Burks A.W. et al.Guidelines for the diagnosis and management of food allergy in the United States: summary of the NIAID-sponsored expert panel report.J Allergy Clin Immunol. 2010; 126: S1-58PubMed Google Scholar In this review we will focus on efforts to treat IgE-mediated forms of food allergy. Although attempts to desensitize patients with food allergy date back more than 100 years, such as oral immunotherapy (OIT),10Schofield A.T. A case of egg poisoning.Lancet. 1908; 1: 716Abstract Scopus (94) Google Scholar there are no accepted therapies proved to accelerate the development of oral tolerance or to provide effective protection from unintentional exposures.1Sicherer S.H. Sampson H.A. Food allergy: recent advances in pathophysiology and treatment.Annu Rev Med. 2009; 60: 261-277Crossref PubMed Scopus (208) Google Scholar However, a number of therapeutic strategies are under investigation targeting foods that most frequently provoke severe IgE-mediated anaphylactic reactions (peanut, tree nuts, and shellfish) or are most common in children, such as cow's milk and hen's egg.11Wang J. Sampson H.A. Food allergy: recent advances in pathophysiology and treatment.Allergy Asthma Immunol Res. 2009; 1: 19-29Crossref PubMed Scopus (53) Google Scholar Approaches being pursued are both food allergen specific and nonspecific (Fig 1).12Scurlock A.M. Burks A.W. Jones S.M. Oral immunotherapy for food allergy.Curr Allergy Asthma Rep. 2009; 9: 186-193Crossref PubMed Scopus (36) Google Scholar Allergen-specific approaches include OIT, sublingual immunotherapy (SLIT), and epicutaneous immunotherapy (EPIT; desensitization) with native food allergens and mutated recombinant proteins, which have decreased IgE-binding activity, coadministered within heat-killed Escherichia coli (HKE) to generate maximum immune response. Diets containing extensively heated (baked) food, such as milk or egg, might represent an alternative approach to allergen-specific immunomodulation of food allergy in some patients.Nonspecific approaches include anti-IgE mAbs, which might increase the threshold dose for reactivity to food allergens, and a Chinese herbal formulation, which prevented peanut-induced anaphylaxis in a murine model of peanut-induced anaphylaxis and is currently being investigated in clinical trials.Selection of candidates for novel food allergy therapiesFood allergies seriously alter the quality of life of patients with food allergy and their families. Fortunately, about 85% of children allergic to foods such as cow's milk, egg, wheat and other cereal grains, and soy “outgrow” (develop tolerance) their allergy, whereas only 15% to 20% of children allergic to peanut, tree nuts, fish, and shellfish will show spontaneous tolerance. Diagnostic tests are needed that can distinguish subjects with transient from persistent forms of food allergy so that therapeutic strategies can be used early to accelerate the induction of tolerance in those who can outgrow their allergy or to induce tolerance in those with the persistent form. Currently, there are no diagnostic tests (eg, serum food allergen–specific IgE antibody measurement or skin prick tests) that reliably predict the potential for spontaneous development of oral tolerance. However, 2 recent reports in children with multiple food allergies noted that few children with peak cow's milk– or egg white–specific IgE antibody levels of 50 kUA/L or greater (UniCAP; Phadia, Uppsala, Sweden) outgrow their allergy by their late teenage years.13Skripak J.M. Matsui E.C. Mudd K. Wood R.A. The natural history of IgE-mediated cow's milk allergy.J Allergy Clin Immunol. 2007; 120: 1172-1177Abstract Full Text Full Text PDF PubMed Scopus (592) Google Scholar, 14Savage J.H. Matsui E.C. Skripak J.M. Wood R.A. The natural history of egg allergy.J Allergy Clin Immunol. 2007; 120: 1413-1417Abstract Full Text Full Text PDF PubMed Scopus (451) Google Scholar In addition, recent studies using peptide microarray assays to determine the diversity and affinity of IgE binding to sequential epitopes on major food allergens (eg, peanut, cow's milk, and egg white) might be useful in determining the severity and persistence of food allergy in affected patients (Table I).15Cooke S.K. Sampson H.A. Allergenic properties of ovomucoid in man.J Immunol. 1997; 159: 2026-2032PubMed Google Scholar, 16Jarvinen K.M. Beyer K. Vila L. Bardina L. Mishoe M. Sampson H.A. Specificity of IgE antibodies to sequential epitopes of hen's egg ovomucoid as a marker for persistence of egg allergy.Allergy. 2007; 62: 758-765Crossref PubMed Scopus (218) Google Scholar, 17Jarvinen K.M. Chatchatee P. Bardina L. Beyer K. Sampson H.A. IgE and IgG binding epitopes on alpha-lactalbumin and beta-lactoglobulin in cow's milk allergy.Int Arch Allergy Immunol. 2001; 126: 111-118Crossref PubMed Scopus (255) Google Scholar, 18Wang J. Lin J. Bardina L. et al.Correlation of IgE/IgG4 milk epitopes and affinity of milk-specific IgE antibodies with different phenotypes of clinical milk allergy.J Allergy Clin Immunol. 2010; 125: 695-702Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, 19Shreffler W.G. Beyer K. Chu T.H. Burks A.W. Sampson H.A. Microarray immunoassay: association of clinical history, in vitro IgE function, and heterogeneity of allergenic peanut epitopes.J Allergy Clin Immunol. 2004; 113: 776-782Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar, 20Flinterman A.E. Knol E.F. Lencer D.A. et al.Peanut epitopes for IgE and IgG4 in peanut-sensitized children in relation to severity of peanut allergy.J Allergy Clin Immunol. 2008; 121: 737-743Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 21Chatchatee P. Jarvinen K.M. Bardina L. Beyer K. Sampson H.A. Identification of IgE- and IgG-binding epitopes on alpha(s1)-casein: differences in patients with persistent and transient cow's milk allergy.J Allergy Clin Immunol. 2001; 107: 379-383Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar, 22Jarvinen K.M. Beyer K. Vila L. Chatchatee P. Busse P.J. Sampson H.A. B-cell epitopes as a screening instrument for persistent cow's milk allergy.J Allergy Clin Immunol. 2002; 110: 293-297Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar, 23Cerecedo I. Zamora J. Shreffler W.G. et al.Mapping of the IgE and IgG4 sequential epitopes of milk allergens with a peptide microarray-based immunoassay.J Allergy Clin Immunol. 2008; 122: 589-594Abstract Full Text Full Text PDF PubMed Scopus (151) Google ScholarTable ISignificance of sequential IgE-binding epitopes in egg white, cow's milk, and peanutPatient population and methodsResultsEgg white ovomucoid Cooke and Sampson, 199715Cooke S.K. Sampson H.A. Allergenic properties of ovomucoid in man.J Immunol. 1997; 159: 2026-2032PubMed Google ScholarChildren with persistent egg allergy and atopic dermatitis: ovomucoid dodecapeptides overlapping by 10 amino acids were synthesized on a SPOTs membrane.Serum from a subject with transient egg allergy had no IgE antibodies against reduced and alkylated (sequential epitopes) ovomucoid, whereas serum from a subject with persistent egg allergy recognized sequential ovomucoid epitopes. Jarvinen et al, 200716Jarvinen K.M. Beyer K. Vila L. Bardina L. Mishoe M. Sampson H.A. Specificity of IgE antibodies to sequential epitopes of hen's egg ovomucoid as a marker for persistence of egg allergy.Allergy. 2007; 62: 758-765Crossref PubMed Scopus (218) Google ScholarEleven children with transient and 7 children with persistent egg allergy: the central decapeptides from each of the major IgE-binding epitopes of ovomucoid synthesized on a SPOTs membrane: Immunolabeling was done with individual patients' sera.Both groups had comparable ranges of egg-specific IgE levels, but none of the patients with transient egg allergy had IgE antibodies against these epitopes of ovomucoid: amino acids 1-10, 11-20, 47-56, and 113-122. In contrast, all 7 patients with persistent egg allergy recognized at least 4 of these immunodominant epitopes.Milk Jarvinen et al, 200117Jarvinen K.M. Chatchatee P. Bardina L. Beyer K. Sampson H.A. IgE and IgG binding epitopes on alpha-lactalbumin and beta-lactoglobulin in cow's milk allergy.Int Arch Allergy Immunol. 2001; 126: 111-118Crossref PubMed Scopus (255) Google ScholarTen patients with persistent milk allergy and 10 patients who subsequently outgrew their milk allergy: 25 decapeptides of αs1-casein, αs2-casein, κ-casein, α-lactalbumin, and β-lactoglobulin, comprising the core epitopes, synthesized on a SPOTs membrane. Sera from individual patients were used for immunolabeling.Five IgE-binding epitopes (2 on α (s1)-casein, 1 on α (s2)-casein, and 2 on κ-casein) were not recognized by any of the patients with transient milk allergy but showed binding by the majority of the patients with persistent allergy. Antibodies against at least 1 of 3 epitopes (amino acids 123-132 on αs1-casein, amino acids 171-180 on αs2-casein, and amino acids 155-164 on κ-casein) were identified in all patients with persistent milk allergy. Wang et al, 201018Wang J. Lin J. Bardina L. et al.Correlation of IgE/IgG4 milk epitopes and affinity of milk-specific IgE antibodies with different phenotypes of clinical milk allergy.J Allergy Clin Immunol. 2010; 125: 695-702Abstract Full Text Full Text PDF PubMed Scopus (169) Google ScholarThirty-three children with milk allergy and 8 children who outgrew milk allergy. Peptides, consisting of 20 amino acids overlapping by 17 (3-offset) and corresponding to the primary sequences of αs1-, αs2-, β-, and κ-caseins and β-lactoglobulin, were arrayed on glass slides.Subjects with milk allergy had increased epitope diversity compared with those who outgrew milk allergy. Binding to higher numbers of IgE peptides was associated with more severe allergic reactions during challenge. In a competitive peptide microarray assay, allergic patients demonstrated a combination of high- and low-affinity IgE binding, whereas subjects who had outgrown their milk allergy had primarily low-affinity binding.Peanut Ara h 1, Ara h 2, Ara h 3 (peptide microarray) Shreffler et al, 200419Shreffler W.G. Beyer K. Chu T.H. Burks A.W. Sampson H.A. Microarray immunoassay: association of clinical history, in vitro IgE function, and heterogeneity of allergenic peanut epitopes.J Allergy Clin Immunol. 2004; 113: 776-782Abstract Full Text Full Text PDF PubMed Scopus (301) Google ScholarSeventy-seven patient and 15 control sera were analyzed. A set of 213 overlapping 20-residue peptides was synthesized, corresponding to the primary sequences of Ara h 1, Ara h 2, and Ara h 3. Peptides were arrayed in triplicate along with the corresponding recombinant proteins onto glass slides and used for immunolabeling.The majority of patients (97%) had specific IgE to at least 1 of the recombinant allergens; 87% had detectable IgE to sequential epitopes. Individual patients had significant heterogeneity in the numbers and patterns of epitopes recognized. High epitope diversity was found in patients with a history of more severe allergic reactions. Flinterman, 200820Flinterman A.E. Knol E.F. Lencer D.A. et al.Peanut epitopes for IgE and IgG4 in peanut-sensitized children in relation to severity of peanut allergy.J Allergy Clin Immunol. 2008; 121: 737-743Abstract Full Text Full Text PDF PubMed Scopus (172) Google ScholarTwenty-four peanut-sensitized children and 6 atopic control subjects: specific IgE and IgG4 binding to 419 overlapping 15-amino-acid peptides representing the sequence of recombinant Ara h 1, Ara h 2, and Ara h3 was analyzed with a microarray immunoassay.Peanut-sensitized sera bound significantly more IgE and IgG4 epitopes than control sera. There was a positive correlation between the number of IgE epitope recognized and clinical sensitivity (r = 0.6, P = .021). IgE and IgG4 epitope-recognition patterns were stable over a 20-month period. Open table in a new tab Immunotherapeutic approaches for treating food allergyPatients with food allergy can be divided into 3 basic phenotypes: transient food allergy, persistent food allergy, and food-pollen (oral allergy) syndrome. Based on developing evidence, it appears that each of these forms of IgE-mediated food allergy is the result of different immunologic mechanisms and therefore is likely to require different immunotherapeutic approaches to bring about resolution.It appears that patients with transient food allergy will have the most favorable response to therapy. Although it might be argued that transient food allergy does not require treatment, the potential benefits of therapy include accelerated development of tolerance and improved quality of life and nutrition.Persistent food allergy might present a more challenging situation. Patients with the persistent form of food allergy are likely to have a less favorable response to therapy, including failure to desensitize, failure to have oral tolerance, need for a more prolonged treatment course, and development of more serious adverse reactions during therapy. As experience with various treatment regimens increases, we will be better equipped to counsel patients about optimal individualized therapeutic options.Allergen-specific immunotherapyDiet containing extensively heated milk and eggSeveral studies have demonstrated that children with transient egg and milk allergy produce IgE antibodies directed primarily against conformational IgE-binding epitopes that are destroyed during extensive heating or food processing.15Cooke S.K. Sampson H.A. Allergenic properties of ovomucoid in man.J Immunol. 1997; 159: 2026-2032PubMed Google Scholar, 16Jarvinen K.M. Beyer K. Vila L. Bardina L. Mishoe M. Sampson H.A. Specificity of IgE antibodies to sequential epitopes of hen's egg ovomucoid as a marker for persistence of egg allergy.Allergy. 2007; 62: 758-765Crossref PubMed Scopus (218) Google Scholar Based on these observations, we hypothesized that children with transient milk and egg allergy, which comprises up to 80% of children with milk and egg allergy, would tolerate baked products containing milk and egg. Two clinical trials investigated the tolerance of extensively heated (baked into other products) milk and egg in children with milk and egg allergy.24Nowak-Wegrzyn A. Bloom K.A. Sicherer S.H. et al.Tolerance to extensively heated milk in children with cow's milk allergy.J Allergy Clin Immunol. 2008; 122: 342-347Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar, 25Lemon-Mule H. Sampson H.A. Sicherer S.H. Shreffler W.G. Noone S. Nowak-Wegrzyn A. Immunologic changes in children with egg allergy ingesting extensively heated egg.J Allergy Clin Immunol. 2008; 122: 977-983Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar In both studies approximately 80% of children tolerated extensively heated milk and egg products during an initial physician-supervised oral challenge. Severe reactions that required treatment with epinephrine occurred only in children who reacted to the extensively heated milk products but not in children who tolerated extensively heated milk and reacted to unheated milk. In contrast, there was no such distinction in children reacting to extensively heated or unheated egg products.Food-specific IgE levels and skin prick test responses were not reliable markers for identifying children tolerant to extensively heated milk or egg, and oral food challenges were necessary. However, the majority of children who reacted to extensively heated milk had milk-specific IgE antibody levels of greater than 35 kUA/L (UniCAP, Phadia). In a study conducted in a different patient population, a positive decision point for reactivity to heated egg was 10.8 kUA/L, and the negative decision point was 1.2 kUA/L (UniCAP, Phadia).26Ando H. Moverare R. Kondo Y. et al.Utility of ovomucoid-specific IgE concentrations in predicting symptomatic egg allergy.J Allergy Clin Immunol. 2008; 122: 583-588Abstract Full Text Full Text PDF PubMed Scopus (187) Google ScholarChildren who reacted to extensively heated milk had significantly higher basophil reactivity to stimulation with casein compared with that seen in the extensively heated milk–tolerant children.27Wanich N. Nowak-Wegrzyn A. Sampson H.A. Shreffler W.G. Allergen-specific basophil suppression associated with clinical tolerance in patients with milk allergy.J Allergy Clin Immunol. 2009; 123: 789-794Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar There was a significantly higher median percentage (16.9%; 25th-75th percentile, 7.1% to 31.7%) of proliferating casein-specific CD25+CD27+ T cells from casein-induced PBMC cultures of 18 extensively heated milk–tolerant subjects compared with 8 subjects reactive to extensively heated milk (4.9% [25th-75th percentile, 2.6% to 7.5%], P < .01).28Shreffler W.G. Wanich N. Moloney M. Nowak-Wegrzyn A. Sampson H.A. Association of allergen-specific regulatory T cells with the onset of clinical tolerance to milk protein.J Allergy Clin Immunol. 2009; 123: 43-52Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar There were no significant differences between the groups in the frequency of polyclonal T cells or casein-specific effector T cells. Casein-specific regulatory T cells were forkhead box protein 3 (FoxP3)–positive, CD25hi, CD27+, cytotoxic T lymphocyte–associated antigen 4–positive, CD45RO+, and CD127−. Depletion of the CD25hi cells before in vitro culture significantly enhanced casein-specific effector T-cell expansion, confirming the presence of greater regulatory T-cell activity. A higher frequency of casein-specific regulatory T cells correlated with a phenotype of mild transient milk allergy and favorable prognosis.Baked goods with milk or egg were added to the diets of tolerant children, who were followed up every 3 to 6 months. No increases were seen in acute allergic reactions or in the severity of underlying atopic diseases, such as asthma, atopic dermatitis, or eczema. There was no increase in the intestinal permeability (determined with measurement of a urinary clearance of lactulose and mannitol) over the first year on the diet and no negative effects on growth. Immunologic changes observed after the introduction of baked goods with milk and egg into the diet included increasing food-specific IgG4 antibodies, decreasing wheal sizes on skin prick tests, and a trend for decreasing food-specific IgE antibody levels, findings similar to those observed in patients undergoing OIT. Preliminary findings suggest that many of the children started on baked products experience accelerated tolerance induction, and a large study is ongoing to establish the safety and efficacy of introducing baked products into the diets of tolerant children as a form of immunotherapy.Subcutaneous peanut immunotherapySubcutaneous immunotherapy has been used for more than 100 years to treat environmental allergies. In a study using an aqueous extract of peanut, 3 actively treated subjects displayed a 67% to 100% decrease in symptoms during double-blind, placebo-controlled food challenges (DBPCFCs) and had a 2- to 5-log reduction in end point skin prick test reactivity to peanut at the end of the treatment course, whereas 1 placebo-treated subject had no change in these parameters.29Oppenheimer J.J. Nelson H.S. Bock S.A. Christensen F. Leung D.Y. Treatment of peanut allergy with rush immunotherapy.J Allergy Clin Immunol. 1992; 90: 256-262Abstract Full Text PDF PubMed Scopus (435) Google Scholar As a consequence of a pharmacy error, 1 placebo-treated subject died of anaphylaxis after administration of a dose of peanut extract, resulting in the termination of the study. This tragic event highlighted the serious risks of peanut immunotherapy.In a follow-up study 6 subjects were treated with a maintenance dose of 0.5 mL of 1:100 wt/vol peanut extract, and 6 were followed as an observational untreated control group for 12 months.30Nelson H.S. Lahr J. Rule R. Bock A. Leung D. Treatment of anaphylactic sensitivity to peanuts by immunotherapy with injections of aqueous peanut extract.J Allergy Clin Immunol. 1997; 99: 744-751Abstract Full Text PDF PubMed Scopus (504) Google Scholar At the end of 12 months, all 6 treated subjects tolerated an increased peanut threshold dose during oral food challenges and had decreased sensitivity on titrated peanut skin prick tests, whereas untreated control subjects experienced no improvement in these parameters. However, anaphylaxis with respiratory involvement was provoked a mean of 7.7 times during the rush phase (23% of the doses), with an average of 9.8 epinephrine injections per subject treated with peanut immunotherapy. Only 3 of 6 subjects were able to achieve the intended maintenance dose because of frequent adverse reactions. During the maintenance phase, the rate of systemic reactions was 39%, with an average of 12.6 epinephrine injections per subject. Although this study provided evidence that injected food allergen could induce desensitization, the high rate of unpredictable severe adverse reactions discouraged further evaluation of this form of therapy.Immunotherapy with pollen for the cross-reactive foodThe concept of cross-immunotherapy has been applied to the pollen-food allergy syndrome (PFAS; also referred to as oral allergy syndrome). Several studies showed variable beneficial effects on oral symptoms and skin test reactivity to certain plant foods in subjects treated with pollen subcutaneous immunotherapy or SLIT.31Asero R. Effects of birch pollen-specific immunotherapy on apple allergy in birch pollen-hypersensitive patients.Clin Exp Allergy. 1998; 28: 1368-1373Crossref PubMed Scopus (199) Google Scholar, 32Asero R.