Maternal supplementation with α-tocopherol inhibits the development of offspring food allergy, H1R signaling and ultimately anaphylaxis early in life
Food allergy has had a rapid rise in prevalence, and thus it is important to identify approaches to limit the development of food allergy early in life. Because maternal dietary supplementation with α-tocopherol (α-T), an isoform of vitamin E, during pregnancy and nursing increases neonate plasma levels of α-T and can limit neonate development of other allergies, we hypothesized that α-T can limit development of food allergy. To assess this, male mice with mutations in their skin barrier genes (FT−/− mice) were mated with wild-type females that received a diet supplemented with α-tocopherol or a control diet. Starting at postnatal day 3, these FT+/− pups were sensitized 4 to 5 times over 2.5 weeks by skin co-exposure to the food allergen peanut extract (PNE) and the environmental allergen Alternaria alternata (Alt). Control pups were exposed to saline, PNE only or Alt only. Supplementation with α-T blocked Alt+PNE sensitization (anti-PNE-specific IgE), without blocking Alt+PNE-stimulated skin IL33, Areg, OSM, CCL11, TSLP or plasma MCPT1. However, supplementation with α-T blocked mast cell activation, the increase in plasma histamine in Alt+PNE sensitized pups, histamine receptor stimulation of endothelial PKCα signaling, and ultimately oral PNE-induced anaphylaxis in Alt+PNE sensitized mice. Thus, maternal supplementation with α-tocopherol reduced development of food allergy and anaphylaxis in neonates. These results have implications for supplementation of mothers with α-tocopherol to limit development of food allergy in neonates with skin barrier mutations.
https://doi.org/10.1093/jimmun/vkae041
Enhancing the diagnostic accuracy of the IgE crosslinking-induced luciferase expression (EXiLE) method for walnut allergy
Background: Walnut (Juglans regia) frequently triggers nut allergies in the United Kingdom and in the United States, with increasing cases in Japan. While oral food challenges (OFCs) are the definitive method for diagnosing these allergies, they pose the risk of symptom provocation, necessitating safer alternative tests. Our aim here was to evaluate the diagnostic utility of IgE (immunoglobulin E) crosslinking-induced luciferase expression (EXiLE) for walnut allergy compared with the walnut-specific IgE (sIgE) test, Jug r 1-sIgE test, and skin prick test (SPT). Methods: This retrospective study analyzed 55 patients tested for walnut allergy (WA) at Fujita Health University Bantane Hospital from January 2021 to December 2023. Among them, 38 had allergic reactions to walnuts based on history or OFCs and 17 did not. We evaluated the sensitivity, specificity, positive predictive value, negative predictive value, and the area under the curve (AUC) of the receiver operating characteristic curve. Results: The EXiLE method (AUC = 0.938) exhibited superior diagnostic accuracy compared to the walnut-sIgE and comparable performance to Jug r 1-sIgE and SPT. The optimal cutoff value of 1.26-fold change demonstrated high sensitivity (0.92), specificity (0.88), positive predictive value (0.92), and negative predictive value (0.82). The EXiLE method yielded positive results in all three cases with negative Jug r 1-sIgE (< 0.35 UA/mL). Conclusion: The EXiLE method showed high sensitivity and specificity for diagnosing WA, indicating its potential clinical utility. Furthermore, the combination of Jug r 1-sIgE and EXiLE may enhance diagnostic accuracy. Future large-scale studies are warranted to confirm these findings and establish comprehensive diagnostic protocols.
https://doi.org/10.15586/aei.v53i2.1267
The prevalence of peanut-triggered food protein-induced enterocolitis syndrome in a prospective cohort of infants introducing peanut in the first year of life
Background: Since the early introduction of peanut to prevent IgE-mediated peanut allergy, other case series have suggested an increased incidence of peanut-triggered Food Protein Induced Enterocolitis Syndrome (FPIES). Data on the prevalence of peanut-induced FPIES in prospective cohorts are lacking. Methods: The PeanutNL cohort is a prospective cohort that included infants at risk of peanut allergy (n = 706) as well as infants with reactions to peanut at home after early introduction (n = 186). They all introduced peanut before the age of 12 months. Oral food challenges were performed to introduce peanut or to evaluate reactions to peanut at home. Results: Of the 706 infants that were included for first introduction of peanut, 2 had reactions with a phenotype compatible with FPIES (0.3%). Of the 186 infants with reactions to peanut at home, 6 were diagnosed with FPIES (3.2%). Seven out of 8 cases had ingestions of peanut without reactions at home or during clinical introduction before FPIES became apparent. During a 3-year follow-up, six infants (75%) were shown to be tolerant to peanut before the age of 3 years. Conclusion: The prevalence of challenge-proven peanut-induced FPIES in a Dutch cohort of atopic infants that introduced peanut between the ages of 4 and 11 months is 0.3%. The majority of cases were tolerant to peanut before the age of 3 years. When introducing peanut in the first year of life, physicians should be aware of FPIES reactions, but it should not be a reason to avoid early introduction of peanut.
https://doi.org/10.1111/pai.70058
Basophil Activation Test for the Improved Diagnosis of Peanut and Tree Nut Allergy
Purpose of review: As an ex-vivo test of allergic effector cell activation, basophil activation testing (BAT) to allergen enables quantification of the in-vivo IgE-mediated allergic response. BAT thus holds promise in the diagnosis and monitoring of peanut and tree nut allergies. Recent systematic analyses and expert recommendations support a role for BAT in the diagnosis of peanut and tree nut allergy. Recent findings: Diagnostic cut-offs for BAT in peanut and tree nut allergy have been identified. Consistently, BAT can discriminate with high sensitivity and specificity between allergy and tolerance when measured against oral food challenges. Furthermore, the utilization of BAT has can increase the sensitivity and specificity of peanut allergy and tree nut allergy diagnosis, both alone and in conjunction with specific IgE testing and skin prick testing. BAT is a promising tool in the diagnosis of peanut and tree nut allergy.
https://doi.org/10.1007/s11882-025-01200-1
Efficacy and Safety of Epicutaneous Immunotherapy in Peanut-Allergic Toddlers: Open-Label Extension to EPITOPE
Background: The pivotal phase 3 EPITOPE trial, a 12-month, double-blind, placebo-controlled study of epicutaneous immunotherapy with the VIASKIN® patch containing 250 μg peanut protein (VP250) previously reported significant treatment response vs placebo in peanut-allergic toddlers aged 1-through-3 years. Objective: To assess interim efficacy and safety of VP250 from the first year of the EPITOPE open-label extension (OLE) study. Methods: Eligible participants enrolled in the OLE study for up to 3 years of total treatment with annual double-blind, placebo-controlled food challenges (DBPCFC) and safety assessments; here we report the first year OLE (Year 2) results. Results: 266 EPITOPE participants enrolled in the OLE study; 244 underwent Month 24 DBPCFC (n=166 VP250; n=78 placebo). After 24 months of VP250, 81.3% reached an eliciting dose (ED) ≥1000 mg, 63.8% reached an ED ≥2000 mg, and 55.9% completed the DBPCFC (cumulative dose: 3444 mg) without meeting stopping criteria. No treatment-related anaphylaxis or serious treatment-related adverse events occurred during Year 2 in this treatment arm. Local application-site reactions occurred less frequently in Year 2 vs Year 1. In placebo-treated EPITOPE participants, outcomes after 1 year of open-label VP250 were consistent with EPITOPE treatment results: 62.7% reached an ED ≥1000 mg, 36.5% reached an ED ≥2000 mg, and 28.4% completed the DBPCFC without meeting stopping criteria; and there was 1 treatment-related anaphylaxis event. Conclusions: Two years of VP250 in young peanut-allergic children demonstrated continued treatment effect increases without new safety signals. This supports the potential of VP250 as a safe and effective treatment for peanut allergy in young children.
https://doi.org/10.1016/j.jaip.2025.02.004
Hazelnut oral immunotherapy desensitizes hazelnut but not other tree nut allergies (Nut CRACKER Study)
Background: Data on oral immunotherapy (OIT) for hazelnut allergy is limited and its potential to cross-desensitize for other nuts is unknown. Objective: To study the efficacy and safety of hazelnut OIT in desensitizing hazelnut and additional tree nuts. Methods: A prospective observational study of 30 hazelnut allergic patients aged ≥4 years who underwent hazelnut OIT. Full desensitization (4000 mg protein) rates were compared to 14 observational controls, and immunological changes during OIT were measured. Cross-desensitization was determined in cases of walnut and cashew co-allergy (n=12). Inhibition of IgE binding to walnut by hazelnut was evaluated in a separate set of walnut-hazelnut dual allergic patients, by ELISA. Results: The rate of full hazelnut desensitization following OIT was 96.7% (29/30) compared to 14.3% (2/14) in controls (OR=25.7, 95% CI 3.7-178.7, p<0.001). Five patients (16.7%) were treated with injectable epinephrine for home reactions. Hazelnut SPT and sIgE to hazelnut and its main components, Cor a 9, 14 and 16, decreased while sIgG4 increased during OIT. A maintenance dose of 1200 mg hazelnut protein was sufficient to maintain full desensitization. No cross-desensitization was noted in dual hazelnut-cashew allergic patients (n=6). In dual hazelnut-walnut allergic patients, an increase in the walnut eliciting dose was observed in 2/6 (33.2%) patients (to 1200 and 4200 mg, respectively). Similarly, by cross-inhibition ELISA, hazelnut competed for IgE-binding to walnut in 5/25 (20%) hazelnut-walnut co-allergic patients. Conclusions: Hazelnut OIT is highly effective, with a similar safety profile as OIT to other nuts. Cross-desensitization to walnut and cashew is unlikely.
https://doi.org/10.1016/j.jaip.2024.12.041
Ara h 2-expressing cucumber mosaic virus-like particle (VLP Peanut) induces in vitro tolerogenic cellular responses in peanut-allergic individuals
Background: Peanut allergy (PA) is one of the most prevalent food allergies with a lack of favorable safety/efficacy treatment. A cucumber mosaic virus-like particle expressing peanut allergen component Ara h 2 (VLP Peanut) has been developed as a novel therapeutic approach for PA. Objective: We assessed the tolerogenic properties and reactivity of VLP Peanut. Methods: Whole blood and peripheral blood mononuclear cells were collected from 6 peanut-allergic children. Modulation of dendritic cells (DCs), T cells, and B cells, stimulated with VLP Peanut, Ara h 2, and whole peanut extract in vitro, were assessed by quantitative real-time PCR and flow cytometry, respectively. Basophil and skin reactivity in response to VLP Peanut was assessed by basophil activation test and skin prick test, respectively. Results: VLP Peanut showed beneficial biochemical properties, fit for use in clinical studies. VLP Peanut induced IFN-γ+ TH1 (P < .05) while having reduced capacity to elicit proliferation of TH2, allergen-specific TH2, and IL-4+-T follicular helper cells. Moreover, VLP Peanut is associated with upregulation of DC1-associated genes (MX1) compared to Ara h 2 and whole peanut extract. VLP Peanut was the most prominent at inducing IL-10+ regulatory B cells (P < .05). Unbiased clustering analyses identified metaclusters of T and B cells targeted by VLP Peanut. Finally, VLP Peanut had reduced capacity to elicit high- and low-affinity IgE receptor-mediated responses compared to Ara h 2 or whole peanut extract (all P < .05). Finally, in an open-label first-in-human cohort of 6 peanut-allergic adults, administration of increasing concentration of VLP Peanut through skin prick test was tolerated and demonstrated no development of skin reactivity. Conclusions: VLP Peanut displayed tolerogenic properties by modulating DCs, T cells, and B cells in vitro. Preliminary findings of skin reactivity using VLP Peanut in 6 peanut-allergic adults was safe and well tolerated in an open-label phase 1 study.
https://doi.org/10.1016/j.jaci.2024.08.010
Peanut Oral Immunotherapy in Children with High-Threshold Peanut Allergy
Background: Approved therapeutics for peanut allergy are not designed for the many patients with allergic reactions to more than one peanut. Methods: We randomly assigned (1:1) participants 4 to 14 years of age reacting to a challenge of between 443 mg and 5043 mg of peanut protein to peanut oral immunotherapy (P-OIT) using home-measured peanut butter versus peanut avoidance. The primary end point was the difference between groups in the proportion tolerating a two-dose-level increase or 9043 mg of peanut protein. For ingestion participants tolerating 9043 mg, sustained unresponsiveness (tolerance off treatment) was tested after 16 weeks of ad lib ingestion followed by 8 weeks of abstinence. Results: Of 73 participants, 38 were randomly assigned to P-OIT and 35 to avoidance. Thirty-two of 38 participants in the ingestion group (84.2%) and 30 of 35 in the avoidance group (85.7%) underwent the primary outcome food challenge. The primary analysis with prespecified multiple imputation for missing values showed 100% success for ingestion versus 21.0% for avoidance (between-group difference, 79.0 percentage points; 95% confidence interval [CI], 64.6 to 93.5; P<0.001). All 32 treated and 3 out of 30 avoiders (10%) tolerated 9043 mg. In the intention-to-treat analysis, sustained unresponsiveness occurred in 68.4% (26/38) on P-OIT versus 8.6% (3/35) tolerating 9043 mg among those avoiding (between-group difference, 59.9 percentage points; 95% CI, 42.4 to 77.3). No dosing reactions were greater than grade 1 severity, and no serious adverse events were reported. Conclusions: In this trial of P-OIT using store-bought, home-measured peanut versus peanut avoidance in high-threshold peanut allergy, those treated achieved significantly higher rates of desensitization with a durable response off treatment. (Funded by the National Center for Advancing Translational Sciences [UL1TR004419] and the National Institute of Allergy and Infectious [U19AI136053]; ClinicalTrials.gov number, NCT03907397.).
https://doi.org/10.1056/EVIDoa2400306
Safety of oral immunotherapy for cashew nut and peanut allergy in children - a retrospective single-centre study
Aim of the study: Oral immunotherapy (OIT) is increasingly used for the treatment of childhood food allergies, with limited data available on cashew nut OIT. This real-life study investigated the safety and feasibility of cashew nut OIT, comparing it with peanut OIT, with a focus on the up-dosing process. Methods: We analysed cashew nut (n = 24) and peanut (n = 38) OIT cases with treatment initiated between 2018 and 2022 at the University Children's Hospital Basel. All patients who commenced therapy within this time frame were enrolled without prior selection. Two different starting protocols were used. Within the up-dosing protocol, the nut intake was incrementally increased by 20-30% every 2 weeks until reaching a maintenance dose of 1 g of nut protein. After consuming the maintenance dose regularly for 18-24 months, a second oral food challenge was performed. Patients who passed this challenge were considered desensitised. The safety of the therapy was evaluated based on the severity of adverse reactions during the up-dosing phase. Symptom severity was evaluated using the validated ordinal food allergy severity scale (o-FASS-5). Results: Over the study period, 33% of cashew nut-allergic and 63% of peanut-allergic patients experienced mild to moderate allergic reactions. Severe allergic reactions occurred in five peanut-allergic children with high baseline allergen-specific IgE levels. Six patients with peanut, and none with cashew nut OIT, discontinued the therapy due to adverse reactions. The mean duration to reach the maintenance phase was longer for children with asthma or another food allergy. Among children who already underwent the second oral food challenge, desensitisation was achieved in 91% (11 out of 12) of cashew nut- and 73% (11 out of 15) of peanut-allergic patients. Conclusion: Cashew nut OIT had a low severity of adverse reactions and was generally well-tolerated. However, patient characteristics influenced side effect risk and treatment duration, emphasising the need for individualised OIT strategies.
https://doi.org/10.57187/s.3691
Development of Cashew and Pistachio Ladders through a Food-Processing Approach
Following successful oral immunotherapy (OIT) for peanut allergy using boiled peanuts (BOPI trial), this study investigated the potential of wet-thermal-processing-induced allergen modification, specifically soaking and boiling (1–4 h) to reduce the allergenicity of cashew and pistachio allergens. In addition, this study provides a foundation of understanding for developing safer forms of cashew/pistachio administration for application in OIT by gradual exposure to increasing doses of modified allergens with reduced potency as an “allergen ladder”. An SDS-PAGE analysis and an intrinsic-fluorescence spectroscopy revealed altered tertiary structures of the allergens, leading to their denaturation and even degradation. Notably, the reduction in both allergen-specific polyclonal IgG and human-specific IgE (sIgE) binding correlated with the treatment time, with the most significant decrease observed after 4 h of boiling. In contrast, shorter soaking treatments showed negligible effects on the IgE-binding capacity of these nuts, therefore indicating a further need for optimization. These findings indicate that extended boiling effectively reduced the amounts of the highly potent allergenic component Ana o 3 in cashew and Pis v 1 in pistachio, as confirmed by ELISA using polyclonal anti-Ana o 3 antibodies, and an immunoblot showed decreased IgE epitope binding in cashew and pistachio allergens, which further modified their allergenic profiles. This approach shows promise as a viable method for offering a safer therapeutic option for cashew/pistachio allergy.
https://doi.org/10.3390/foods13213440