Current food allergy management universally treats all patients with food allergy as being at risk for anaphylaxis (with the exception perhaps of pollen food allergy syndrome). Thus, patients are told to avoid the allergenic food in all potentially allergic forms and amounts. However, research over the past 2 decades has shown that many patients will tolerate small amounts of the allergen without any allergic reaction. Thus, if one were able to identify the threshold of reactivity, this could change management. At the population level, establishing levels at which the vast majority of patients (e.g., 95%) do not react could have public health ramifications, such as altering labeling laws. At the individual patient level, personal threshold levels could determine avoidance strategies, affect quality of life, and alter treatment decisions, e.g., oral immunotherapy starting doses. In this review, threshold data for various allergens and their potential effect on the management of the patient with food allergy are examined.

OBJECTIVE: Previous studies have shown efficacy of early introduction of peanut to prevent peanut allergy. It is currently unknown which diagnostic pathway is optimal after parental-reported reactions to peanut at home after early introduction.
METHODS: The PeanutNL cohort study included high-risk infants that were referred for early introduction of peanut. A subgroup of 186 infants with reactions to peanut at home underwent peanut skin prick tests and a supervised open oral food challenge (OFC) at a median age of 8 months. After a negative OFC, peanut was introduced at home.
RESULTS: Sensitization to peanut was detected in 69% of 186 infants, of which 80% had > 4mm wheals in skin prick tests. An OFC with a cumulative dose of 4.4 gr peanut protein was performed in 163 infants with Sampson severity score grade I-III reactions at home; 120 challenges were negative. Peanut was subsequently introduced at home in infants with a negative challenge outcome. After 6 months, 96% were still eating peanut and 81% ate single portions of 3.0 gr peanut protein. One patient was considered to be peanut allergic after reintroduction of peanut at home.
CONCLUSIONS: These data show that 65% of infants with reported reactions to peanut at home have negative OFCs. In those children, peanut could be introduced safely and 96% were able to consume peanut regularly without reactions. Challenging infants under 12 months of age prevents the misdiagnosis of peanut allergy, and enables safe continued exposure to peanut and the induction of long-term tolerance.

Peanut allergy, a prevalent and potentially severe condition affecting millions worldwide, has been linked to specific human leukocyte antigens (HLAs), suggesting increased susceptibility. Employing an immunoinformatic strategy, we developed a \"logo model\" based on amino acid frequencies in the peptide binding core and used it to predict peptides originating from 28 known peanut allergens binding to HLA-DRB1*03:01, one of the susceptibility alleles. These peptides hold promise for immunotherapy in HLA-DRB1*03:01 carriers, offering reduced allergenicity compared to whole proteins. By targeting essential epitopes, immunotherapy can modulate immune responses with minimal risk of severe reactions. This precise approach could induce immune tolerance with fewer adverse effects, presenting a safer and more effective treatment for peanut allergy and other allergic conditions.

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Peanut allergy has garnered worldwide attention due to its high incidence rate and severe symptoms, stimulating the demand for the ultrasensitive detection method of peanut allergen. Herein, we successfully developed a novel electrochemical aptasensor for ultrasensitive detection Ara h1, a major allergenic protein present in peanuts. A conductive nickel atoms Anchored Hydrogen-Bonded Organic Frameworks (PFC-73-Ni) were utilized as excellent electrocatalysts toward hydroquinone (HQ) oxidation to generate a readable current signal. The developed electrochemical aptasensor offers wide linear range (1-120 nM) and low detection limit (0.26 nM) for Ara h1. This method demonstrated a recovery rate ranging from 95.00% to 107.42% in standard addition detection of non-peanut food samples. Additionally, the developed electrochemical method was validated with actual samples and demonstrated good consistency with the results obtained from a commercial ELISA kit. This indicates that the established Ara h1 detection method is a promising tool for peanut allergy prevention.

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BACKGROUND: Few studies have examined long-term outcomes following oral immunotherapy (OIT); none have examined long-term risks and benefits associated with distinct clinical outcomes (desensitization, remission).
METHODS: Participants completing the probiotic and peanut oral immunotherapy (PPOIT) -003 randomized trial were enrolled in a follow-on study, PPOIT-003LT. Peanut ingestion, reactions, and health-related quality of life (HRQOL) were monitored prospectively. Outcomes at 1-year and 2-years post-treatment were examined by treatment group and by post-OIT clinical outcome (remission, desensitization without remission [DWR], allergic).
RESULTS: 86% (151/176) of eligible children enrolled. Post-treatment peanut ingestion at 2-years post-treatment were similar for PPOIT (86.7%) and OIT (78.7%) groups, both higher than placebo (10.3%). Reactions reduced over time for all treatment and clinical outcome groups (PPOIT 31.7% to 23.3%, OIT 37.7% to 19.7%, placebo 13.8% to 6.9%; remission 27.5% to 15.9%; DWR 57.9% to 36.8%; allergic 11.6% to 7%). At 2-years post-treatment, similar proportions of remission and allergic participants reported reactions (RD 0.09 (95%CI -0.03, 0.20), p = .127), whereas more DWR participants reported reactions than remission (remission vs DWR: RD -0.21 (95%CI -0.39; -0.03), p = .02) and allergic (DWR vs allergic: RD 0.30 (95%CI 0.13, 0.47), p = .001) participants. At 2-years post-treatment, 0% remission versus 5.3% DWR versus 2.3% allergic participants reported adrenaline injector usage. Remission participants had significantly greater HRQOL improvement (adjusted for baseline) compared with both DWR (MD -0.54 (95%CI -0.99, -0.10), p = .017) and allergic (MD -0.82 (95%CI -1.25, -0.38), p < .001).
CONCLUSIONS: By 2-years post-treatment, remission participants reported fewer reactions, less severe reactions and greater HRQOL improvement compared with DWR and allergic participants, indicating that remission is the patient-preferred treatment outcome over desensitization or remaining allergic.

BACKGROUND: Existing therapeutic strategies are challenged by long times to achieve effect and often require frequent administration. Peanut-allergic individuals would benefit from a therapeutic that provides rapid protection against accidental exposure within days of administration while carrying little risk of adverse reactions.
OBJECTIVE: Guided by the repertoire of human IgE mAbs from allergic individuals, we sought to develop a treatment approach leveraging the known protective effects of allergen-specific IgG4 antibodies.
METHODS: We applied our single-cell RNA-sequencing SEQ SIFTER platform (IgGenix, Inc, South San Francisco, Calif) to whole blood samples from peanut-allergic individuals to discover IgE mAbs. These were then class-switched by replacing the IgE constant region with IgG4 while retaining the allergen-specific variable regions. In vitro mast cell activation tests, basophil activation tests, ELISAs, and an in vivo peanut allergy mouse model were used to evaluate the specificity, affinity, and activity of these recombinant IgG4 mAbs.
RESULTS: We determined that human peanut-specific IgE mAbs predominantly target immunodominant epitopes on Ara h 2 and Ara h 6 and that recombinant IgG4 mAbs effectively block these epitopes. IGNX001, a mixture of 2 such high-affinity IgG4 mAbs, provided robust protection against peanut-mediated mast cell activation in vitro as well as against anaphylaxis upon intragastric peanut challenge in a peanut allergy mouse model.
CONCLUSIONS: We developed a peanut-specific IgG4 antibody therapeutic with convincing preclinical efficacy starting from a large repertoire of human IgE mAbs from demographically and geographically diverse individuals. These results warrant further clinical investigation of IGNX001 and underscore the opportunity for the application of this therapeutic development strategy in other food and environmental allergies.

Food allergy (FA) is estimated to impact up to 10% of the population and is a growing health concern. FA results from a failure in the mucosal immune system to establish or maintain immunological tolerance to innocuous dietary antigens, IgE production, and the release of histamine and other mediators upon exposure to a food allergen. Of the different FAs, peanut allergy has the highest incidence of severe allergic responses, including systemic anaphylaxis. Despite the recent FDA approval of peanut oral immunotherapy and other investigational immunotherapies, a loss of protection following cessation of therapy can occur, suggesting that these therapies do not address the underlying immune response driving FA. Our lab has shown that liver-directed gene therapy with an adeno-associated virus (AAV) vector induces transgene product-specific regulatory T cells (Tregs), eradicates pre-existing pathogenic antibodies, and protects against anaphylaxis in several models, including ovalbumin induced FA. In an epicutaneous peanut allergy mouse model, the hepatic AAV co-expression of four peanut antigens Ara h1, Ara h2, Ara h3, and Ara h6 together or the single expression of Ara h3 prevented the development of a peanut allergy. Since FA patients show a reduction in Treg numbers and/or function, we believe our approach may address this unmet need.

UNASSIGNED: Peanut allergy (PA) is an IgE-mediated food allergy with variable clinical outcomes. Mild-to-severe symptoms affect various organs and, often, the gastrointestinal tract. The role of intestine-derived IgE antibodies in astrointestinal PA symptoms is poorly understood. This study aimed to examine fecal IgE responses in PA as a novel approach to patient endotyping.
METHODS: Feces and serum samples were collected from peanut-allergic and healthy children (n=26) to identify IgE and cytokines using multiplex assays. Shotgun metagenomics DNA sequencing and allergen database comparisons made it possible to identify microbial peptides with homology to known allergens.
RESULTS: Compared to controls, fecal IgE signatures showed broad diversity and increased levels for 13 allergens, including food, venom, contact, and respiratory allergens (P<.01-.0001). Overall, fecal IgE patterns were negatively correlated compared to sera IgE patterns in PA patients, with the greatest differences recorded for peanut allergens (P<.0001). For 83% of the allergens recognized by fecal IgE, we found bacterial homologs from PA patients\' gut microbiome (eg, thaumatin-like protein Acinetobacter baumannii vs Act d 2, 109/124 aa identical). Compared to controls, PA patients had higher levels of fecal IgA, IL-22, and auto-IgE binding to their own fecal proteins (P<.001). Finally, levels of fecal IgE correlated with abdominal pain scores (P<.0001), suggesting a link between local IgE production and clinical outcomes.
CONCLUSIONS: Fecal IgE release from the intestinal mucosa could be an underlying mechanism of severe abdominal pain through the association between leaky gut epithelia and anticommensal TH2 responses in PA.