Brian P. Vickery

Clinical efficacy and immune regulation with peanut oral immunotherapy

BACKGROUND Oral immunotherapy (OIT) has been thought to induce clinical desensitization to allergenic foods, but trials coupling the clinical response and immunologic effects of peanut OIT have not been reported. OBJECTIVE The study objective was to investigate the clinical efficacy and immunologic changes associated with OIT. METHODS Children with peanut allergy underwent an OIT protocol including initial day escalation, buildup, and maintenance phases, and then oral food challenge. Clinical response and immunologic changes were evaluated. RESULTS Of 29 subjects who completed the protocol, 27 ingested 3.9 g peanut protein during food challenge. Most symptoms noted during OIT resolved spontaneously or with antihistamines. By 6 months, titrated skin prick tests and activation of basophils significantly declined. Peanut-specific IgE decreased by 12 to 18 months, whereas IgG(4) increased significantly. Serum factors inhibited IgE-peanut complex formation in an IgE-facilitated allergen binding assay. Secretion of IL-10, IL-5, IFN-gamma, and TNF-alpha from PBMCs increased over a period of 6 to 12 months. Peanut-specific forkhead box protein 3 T cells increased until 12 months and decreased thereafter. In addition, T-cell microarrays showed downregulation of genes in apoptotic pathways. CONCLUSION Oral immunotherapy induces clinical desensitization to peanut, with significant longer-term humoral and cellular changes. Microarray data suggest a novel role for apoptosis in OIT.

Oral Immunotherapy for Treatment of Egg Allergy in Children

BACKGROUND For egg allergy, dietary avoidance is the only currently approved treatment. We evaluated oral immunotherapy using egg-white powder for the treatment of children with egg allergy. METHODS In this double-blind, randomized, placebo-controlled study, 55 children, 5 to 11 years of age, with egg allergy received oral immunotherapy (40 children) or placebo (15). Initial dose-escalation, build-up, and maintenance phases were followed by an oral food challenge with egg-white powder at 10 months and at 22 months. Children who successfully passed the challenge at 22 months discontinued oral immunotherapy and avoided all egg consumption for 4 to 6 weeks. At 24 months, these children underwent an oral food challenge with egg-white powder and a cooked egg to test for sustained unresponsiveness. Children who passed this challenge at 24 months were placed on a diet with ad libitum egg consumption and were evaluated for continuation of sustained unresponsiveness at 30 months and 36 months. RESULTS After 10 months of therapy, none of the children who received placebo and 55% of those who received oral immunotherapy passed the oral food challenge and were considered to be desensitized; after 22 months, 75% of children in the oral-immunotherapy group were desensitized. In the oral-immunotherapy group, 28% (11 of 40 children) passed the oral food challenge at 24 months and were considered to have sustained unresponsiveness. At 30 months and 36 months, all children who had passed the oral food challenge at 24 months were consuming egg. Of the immune markers measured, small wheal diameters on skin-prick testing and increases in egg-specific IgG4 antibody levels were associated with passing the oral food challenge at 24 months. CONCLUSIONS These results show that oral immunotherapy can desensitize a high proportion of children with egg allergy and induce sustained unresponsiveness in a clinically significant subset. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00461097.).

A randomized controlled study of peanut oral immunotherapy: Clinical desensitization and modulation of the allergic response

BACKGROUND Open-label oral immunotherapy (OIT) protocols have been used to treat small numbers of patients with peanut allergy. Peanut OIT has not been evaluated in double-blind, placebo-controlled trials. OBJECTIVE To investigate the safety and effectiveness of OIT for peanut allergy in a double-blind, placebo-controlled study. METHODS In this multicenter study, children ages 1 to 16 years with peanut allergy received OIT with peanut flour or placebo. Initial escalation, build-up, and maintenance phases were followed by an oral food challenge (OFC) at approximately 1 year. Titrated skin prick tests (SPTs) and laboratory studies were performed at regular intervals. RESULTS Twenty-eight subjects were enrolled in the study. Three peanut OIT subjects withdrew early in the study because of allergic side effects. During the double-blind, placebo-controlled food challenge, all remaining peanut OIT subjects (n = 16) ingested the maximum cumulative dose of 5000 mg (approximately 20 peanuts), whereas placebo subjects (n = 9) ingested a median cumulative dose of 280 mg (range, 0-1900 mg; P < .001). In contrast with the placebo group, the peanut OIT group showed reductions in SPT size (P < .001), IL-5 (P = .01), and IL-13 (P = .02) and increases in peanut-specific IgG(4) (P < .001). Peanut OIT subjects had initial increases in peanut-specific IgE (P < .01) but did not show significant change from baseline by the time of OFC. The ratio of forkhead box protein 3 (FoxP3)(hi): FoxP3(intermediate) CD4+ CD25+ T cells increased at the time of OFC (P = .04) in peanut OIT subjects. CONCLUSION These results conclusively demonstrate that peanut OIT induces desensitization and concurrent immune modulation. The current study continues and is evaluating the hypothesis that peanut OIT causes long-term immune tolerance.

Sustained unresponsiveness to peanut in subjects who have completed peanut oral immunotherapy

BACKGROUND Although peanut oral immunotherapy (OIT) has been conclusively shown to cause desensitization, it is currently unknown whether clinical protection persists after stopping therapy. OBJECTIVE Our primary objective was to determine whether peanut OIT can induce sustained unresponsiveness after withdrawal of OIT. METHODS We conducted a pilot clinical trial of peanut OIT at 2 US centers. Subjects age 1 to 16 years were recruited and treated for up to 5 years with peanut OIT. The protocol was modified over time to permit dose increases to a maximum of 4000 mg/d peanut protein. Blood was collected at multiple time points. Clinical end points were measured with 5000-mg double-blinded, placebo-controlled food challenges once specific criteria were met. RESULTS Of the 39 subjects originally enrolled, 24 completed the protocol and had evaluable outcomes. Twelve (50%) of 24 successfully passed a challenge 1 month after stopping OIT and achieved sustained unresponsiveness. Peanut was added to the diet. At baseline and the time of challenge, such subjects had smaller skin test results, as well as lower IgE levels specific for peanut, Ara h 1, and Ara h 2 and lower ratios of peanut-specific IgE/total IgE compared with subjects not passing. There were no differences in peanut IgG₄ levels or functional activity at the end of the study. CONCLUSIONS This is the first demonstration of sustained unresponsiveness after peanut OIT, occurring in half of subjects treated for up to 5 years. OIT favorably modified the peanut-specific immune response in all subjects completing the protocol. Smaller skin test results and lower allergen-specific IgE levels were predictive of successful outcome.

Sublingual immunotherapy for peanut allergy: a randomized, double-blind, placebo-controlled multicenter trial

BACKGROUND There are presently no available therapeutic options for patients with peanut allergy. OBJECTIVE We sought to investigate the safety, efficacy, and immunologic effects of peanut sublingual immunotherapy (SLIT). METHODS After a baseline oral food challenge (OFC) of up to 2 g of peanut powder (approximately 50% protein; median successfully consumed dose [SCD], 46 mg), 40 subjects, aged 12 to 37 years (median, 15 years), were randomized 1:1 across 5 sites to daily peanut or placebo SLIT. A 5-g OFC was performed after 44 weeks, followed by unblinding; placebo-treated subjects then crossed over to higher dose peanut SLIT, followed by a subsequent crossover Week 44 5-g OFC. Week 44 OFCs from both groups were compared with baseline OFCs; subjects successfully consuming 5 g or at least 10-fold more peanut powder than the baseline OFC threshold were considered responders. RESULTS After 44 weeks of SLIT, 14 (70%) of 20 subjects receiving peanut SLIT were responders compared with 3 (15%) of 20 subjects receiving placebo (P < .001). In peanut SLIT responders, median SCD increased from 3.5 to 496 mg. After 68 weeks of SLIT, median SCD significantly increased to 996 mg (compared with Week 44, P = .05). The median SCD at the Week 44 Crossover OFC was significantly higher than baseline (603 vs 71 mg, P = .02). Seven (44%) of 16 crossover subjects were responders; median SCD increased from 21 to 496 mg among responders. Of 10,855 peanut doses through the Week 44 OFCs, 63.1% were symptom free; excluding oral-pharyngeal symptoms, 95.2% were symptom free. CONCLUSIONS Peanut SLIT safely induced a modest level of desensitization in a majority of subjects compared with placebo. Longer duration of therapy showed statistically significant increases in the SCD.

Adverse reactions during peanut oral immunotherapy home dosing

To The Editor: Oral immunotherapy (OIT) is increasingly being investigated as a potential treatment for peanut and other food allergies, with a recent study demonstrating evidence of clinical desensitization and immunologic changes suggesting the development of long-term tolerance1. Unlike traditional subcutaneous immunotherapy for inhalant allergens, peanut OIT is administered daily, with the vast majority of doses given at home. In our peanut OIT protocols, subjects are seen in the research unit for observed dose escalations every two weeks, and subsequent doses are given at home. In the open-label study of peanut OIT, home doses were generally well-tolerated2. The incidence of allergic reactions with any home dose was 3.5%, with mild upper respiratory and skin symptoms being the most common complaints. Despite the infrequent incidence of symptoms with peanut OIT home dosing, certain patterns of reactions have surfaced during this phase. Characterizing these reactions and identifying potential triggers or factors which predispose to reactions may improve the safety of home dosing. Reactions occurring during investigational OIT or any immunotherapy protocol are challenging to study prospectively, due to ongoing modifications in the protocol and recommendations that are instituted to prevent further reactions. In subcutaneous aeroallergen immunotherapy, asthma has been identified as a risk factor for systemic reactions, prompting recommendations to evaluate respiratory symptoms and consider objective measures of airway function during administration3. Researchers studying milk and egg OIT noted certain “augmentation factors” that lowered threshold doses – namely, infection, exercise, pollen allergy, and irregular intake4 – and identifying these factors and reducing the immunotherapy dose prevented further allergic reactions. We have noted five patterns associated with a propensity to react to a previously tolerated dose of peanut OIT, including several not previously described. It is interesting that these factors would provoke symptoms after a given OIT dose when, in many of the examples noted, the dose had been tolerated for weeks to months without symptoms. Table I lists selected examples illustrating the observed patterns – (1) concurrent illness, (2) suboptimally-controlled asthma, (3) timing of dose administration after food ingestion, (4) physical exertion after dosing, and (5) dosing during menses. Addressing these factors (see Table II) has improved the safety profile of our peanut OIT protocol. While some of our recommendations mirror those instituted in subcutaneous immunotherapy protocols, most are unique to OIT administration. We expand on reports from other research centers4, 5, which have described triggers such as infection, exercise, pollen allergy, and irregular intake, and this is the first report involving protocols for peanut allergy. Table I Examples of Reactions during Peanut OIT Home Dosing Table II Recommendations for Future OIT Investigations We have observed that dosing during febrile illnesses has been associated with systemic reactions to previously tolerated peanut OIT doses. We recommend withholding OIT during acute illnesses and advise subjects to resume dosing at home if fewer than three doses are missed. If three to five doses are missed, subjects return to the research unit for observed dosing. Those who miss more than five days of dosing may require significant dose reduction or repeat desensitization. In our open-label study2, asthma was associated with a higher rate of chest symptoms during OIT. Of the subjects reporting chest symptoms during home dosing, 82% had co-existing asthma. Several subjects receiving peanut OIT noted cough and wheezing after doses. Some also had chronic cough or exercise-induced respiratory symptoms. Although we did not observe changes in pulmonary function in these subjects, their symptoms improved with the initiation of asthma controller medications (see Table I), highlighting the importance of diagnosing and treating co-morbid atopic conditions. Regular peak flow measurements and pulmonary function testing has been implemented to optimize asthma control. It has not been uncommon for a subject taking a daily OIT dose without eating a meal or snack in the two hours before dosing to have symptoms with a dose that has been previously tolerated; taking the same dose with food the next day and thereafter prevents further reactions. Additionally, several subjects have experienced allergic symptoms with exercise after OIT dosing, and we advise these individuals to avoid exertion for two hours after dosing. Finally, one subject had several systemic reactions when menses was coupled with exercise despite no symptoms with daily dosing in the interval between episodes and was eventually withdrawn from the study. She was not taking other medications (e.g. non-steroidal anti-inflammatory drugs). Of note, she did not have systemic reactions each time she exercised during menses. At this time, the role of menses is unclear, and further study is needed. In the studies to date, peanut and food OIT have a good safety profile, and home dosing is infrequently associated with adverse reactions2, 6. However, allergic symptoms should be expected, and subjects and their families should be counseled about circumstances associated with an increased possibility of reacting to previously tolerated OIT doses. As OIT for food allergy becomes increasingly studied in research settings, implementing these recommendations and modifications can improve the safety of these experimental protocols.

Individualized IgE-based dosing of egg oral immunotherapy and the development of tolerance

BACKGROUND Hens egg allergy is among the most common food allergies in childhood and predicts later development of allergic disease. The optimal efficacy and mechanism(s) of egg allergen immunotherapy are poorly understood. OBJECTIVE To enhance immunologic and clinical outcomes of egg oral immunotherapy (OIT) using a conditionally increased dosing strategy. METHODS In an open-label clinical trial of egg OIT, egg-allergic children ingested daily doses of egg protein that were gradually increased based on the egg white (EW) IgE level. Skin prick test reactivity and EW- and ovomucoid-specific cellular and humoral responses were measured longitudinally. To confirm clinical tolerance, patients underwent double-blinded, placebo-controlled food challenges 1 month after completing the dosing protocol. RESULTS Children aged 3 to 13 years with characteristics of clinical egg allergy were enrolled. All 6 patients who completed the entire protocol developed clinical tolerance to egg during the study. The median wheal diameter on EW skin prick testing decreased from 10 to 2.5 mm during OIT (P = .03). Both EW and ovomucoid IgE levels significantly decreased during the study (median EW IgE level: from 18.8 kU/L at baseline to 3.9 kU/L, P = .03), and corresponding IgG4 levels increased (median EW IgG4 level: from 0.65 mg/L at baseline to 86.15 mg/L, P = .03). Transient increases were seen in egg-induced interleukin 10 (P = .06) and transforming growth factor β (P = .18) levels, and the ratio of T(H)2:T(H)1 cytokine production was decreased (P = .25). CONCLUSIONS Egg OIT is associated with tolerance acquisition in children with persistent egg allergy. Individualized dosing regimens may be necessary to achieve a full therapeutic effect in some patients.

Mechanisms of Immune Tolerance Relevant to Food Allergy

The intestine has an unenviable task: to identify and respond to a constant barrage of environmental stimuli that can be both dangerous and beneficial. The proper execution of this task is central to the homeostasis of the host, and as a result, the gastrointestinal tract contains more lymphocytes than any other tissue compartment in the body, as well as unique antigen-presenting cells with specialized functions. When antigen is initially encountered through the gut, this system generates a robust T cell-mediated hyporesponsiveness called oral tolerance. Although seminal observations of oral tolerance were made a century ago, the relevant mechanisms are only beginning to be unraveled with the use of modern investigational techniques. Food allergy is among the clinical disorders that occur from a failure of this system, and therapies that seek to re-establish tolerance are currently under investigation.

Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease

Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder associated with allergic hypersensitivity to food. We interrogated >1.5 million genetic variants in EoE cases of European ancestry and subsequently in a multi-site cohort with local and out-of-study control subjects. In addition to replicating association of the 5q22 locus (meta-analysis P = 1.9 × 10−16), we identified an association at 2p23 spanning CAPN14 (P = 2.5 × 10−10). CAPN14 was specifically expressed in the esophagus, was dynamically upregulated as a function of disease activity and genetic haplotype and after exposure of epithelial cells to interleukin (IL)-13, and was located in an epigenetic hotspot modified by IL-13. Genes neighboring the top 208 EoE-associated sequence variants were enriched for esophageal expression, and multiple loci for allergic sensitization were associated with EoE susceptibility (4.8 × 10−2 < P < 5.1 × 10−11). We propose a model to explain the tissue-specific nature of EoE that involves the interplay of allergic sensitization with an EoE-specific, IL-13–inducible esophageal response involving CAPN14.

Peanut oral immunotherapy modifies IgE and IgG4 responses to major peanut allergens.

BACKGROUND Patients with peanut allergy have highly stable pathologic antibody repertoires to the immunodominant B-cell epitopes of the major peanut allergens Ara h 1 to 3. OBJECTIVE We used a peptide microarray technique to analyze the effect of treatment with peanut oral immunotherapy (OIT) on such repertoires. METHODS Measurements of total peanut-specific IgE (psIgE) and peanut-specific IgG(4) (psIgG(4)) were made with CAP-FEIA. We analyzed sera from 22 patients with OIT and 6 control subjects and measured serum specific IgE and IgG(4) binding to epitopes of Ara h 1 to 3 using a high-throughput peptide microarray technique. Antibody affinity was measured by using a competitive peptide microarray, as previously described. RESULTS At baseline, psIgE and psIgG(4) diversity was similar between patients and control subjects, and there was broad variation in epitope recognition. After a median of 41 months of OIT, polyclonal psIgG(4) levels increased from a median of 0.3 μg/mL (interquartile range [25% to 75%], 0.1-0.43 μg/mL) at baseline to 10.5 μg/mL (interquartile range [25% to 75%], 3.95-45.48 μg/mL; P < .0001) and included de novo specificities. psIgE levels were reduced from a median baseline of 85.45 kU(A)/L (23.05-101.0 kU(A)/L) to 7.75 kU(A)/L (2.58-30.55 kU(A)/L, P < .0001). Affinity was unaffected. Although the psIgE repertoire contracted in most OIT-treated patients, several subjects generated new IgE specificities, even as the total psIgE level decreased. Global epitope-specific shifts from IgE to IgG(4) binding occurred, including at an informative epitope of Ara h 2. CONCLUSION OIT differentially alters Ara h 1 to 3 binding patterns. These changes are variable between patients, are not observed in control subjects, and include a progressive polyclonal increase in IgG(4) levels, with concurrent reduction in IgE amount and diversity.