Limited impact of Der p 23 IgE on treatment outcomes in tablet allergy immunotherapy phase III study.
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ABSTRACT:
SUBMITTER: Stranzl T
PROVIDER: S-EPMC8246736 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:House dust mites (HDMs) are one of the major causes of allergies in the world. The group 23 allergen, Der p 23, from Dermatophagoides pteronyssinus, is a major allergen amongst HDM-sensitized individuals. This study aims to determine the specific immunoglobulin E (sIgE) binding frequency and IgE-binding residues of recombinant Der p 23 (rDer p 23) allergen amongst a cohort of consecutive atopic individuals in a tropical region. We performed site-directed mutagenesis and carried out immuno-dot blot assays using 65 atopic sera. The immuno-dot blot assays results indicated that the two residues K44 and E46 which are located at the N-terminal region are the major IgE-binding residues. The rDerp-23 sIgE titers are strongly correlated to the number of IgE-binding residues for rDer p 23 (P < 0.001). Atopic individuals who were only sensitized to HDM have a significantly higher number of IgE-binding residues than the individuals who were polysensitized to HDM and other crude allergens (P < 0.05). Individuals with allergic multimorbidity and moderate-to-severe allergic rhinitis also have a higher number of IgE-binding residues compared to those with single allergic disease and mild allergic rhinitis. The results prompt us to hypothesize that the individuals who have a higher number of IgE-binding residues may face a bigger challenge to be treated through immunotherapy due to the complexity in designing an effective hypoallergen with a high number of IgE-binding residues. We propose that the development of a refined molecular diagnostic assay, which includes alanine substitution of surface-exposed residues could be a more precise diagnostic strategy to identify all the IgE-binding residues of a major allergen for an atopic individual and the development could be another new dimension in allergy diagnosis and allergen immunotherapy treatment.
| S-EPMC7806929 | biostudies-literature
Project description:BACKGROUND:Due to high IgE recognition frequency and high allergenic activity, Der p 5 and Der p 21 are clinically important house dust mite (HDM) allergens. The objective of this study was to characterize the immunodominant IgE epitopes of Der p 5 and Der p 21 responsible for their high allergenic activity. METHODS:A panel of 12 overlapping peptides spanning the Der p 5 and Der p 21 sequence were synthesized to search for sequential IgE epitopes by direct testing for allergic patients' IgE reactivity. Peptide-specific antibodies raised in rabbits were used in inhibition studies for localizing conformational IgE epitopes which were visualized on the surfaces of the allergen structures by molecular modelling. IgE cross-reactivity between the allergens was investigated by IgE inhibition studies. RESULTS:Immunodominant IgE epitopes defined by allergic patients' IgE on Der p 5 and Der p 21 were primarily of the conformational, discontinuous type including N- and C-terminal portions of the protein. They could be located on each allergen on one area with similar localization, but despite similar structure of the allergens, no relevant IgE cross-reactivity could be detected. CONCLUSION:Our study shows that Der p 5 and Der p 21 contain a major conformational IgE epitope-containing area located on similar portions of their structure, but they lack relevant IgE cross-reactivity. These data are important for the development of modern allergy vaccines based on defined molecules for allergen-specific immunotherapy of HDM allergy.
| S-EPMC6055609 | biostudies-literature
Project description:PurposeMeasurement of IgE specific to purified house dust mite (HDM) allergens may improve allergy diagnosis. This study aimed to investigate the sensitization profiles of Korean HDM allergic subjects suffering from respiratory allergy and atopic dermatitis (AD) to Der f 1, Der f 2, Der f 6, Der f 8, Der f 10, and Der f 20.MethodsRecombinant HDM allergens were produced in Pichia pastoris (Der f 1) or Escherichia coli (5 allergens). IgE reactivity to the individual recombinant allergens and total extract of mite was assessed by ELISA.ResultsDer f 1 was recognized by 79.1%, Der f 2 by 79.1%, Der f 6 by 9.3%, Der f 8 by 6.2%, Der f 10 by 6.2%, and Der f 20 by 6.6% of the patients' sera tested, while the prevalence of IgE reactivity to total mite extract was 94.7%. Combination of Der f 1 and Der f 2 had a sensitivity of 87.6%. Specific IgE to Der f 2 alone was detected from 89.4% of HDM-sensitized respiratory allergy subjects and 92.3% to the combination of the 2 major allergens Der f 1 and Der f 2. However, sera from fewer patients with AD, namely 72.4% and 71.0%, recognized Der f 1 and Der f 2, respectively. The combination of 2 major allergens allowed diagnosis of 84.5% of the AD patients. No correlation between sensitization to specific allergens and HDM allergy entity was found.ConclusionsDer f 2 was the most frequently sensitized allergen among the HDM-sensitized respiratory and AD patients in Korea, and the combination of the group 1 and 2 major allergens increased the diagnostic sensitivity. Minor allergens did not significantly improve diagnostic sensitivity. However, further studies are needed to analyze the relationship between sensitization to other HDM allergens and the disease entity of the HDM allergy.
| S-EPMC4509661 | biostudies-literature
Project description:The majority of allergic patients are poly-sensitized. For causal treatment by allergy immunotherapy (AIT) a single or few allergen products containing the clinically most relevant allergens are applied, but few data on tolerability of multiple application of AIT is available. The aim of our study was to investigate safety and tolerability in patients who started treatment by sublingual immunotherapy (SLIT) with the standardised SQ(®) grass SLIT-tablet and were treated with concomitant AIT products.In a non-interventional, open-label, observational study in Germany treatment of patients with the SQ(®) grass SLIT-tablet and concomitant AIT (SCIT or SLIT) was documented between January 2012 and January 2014. Patients were followed at visits at first administration of the SQ(®) grass SLIT-tablet and after 1-3 months of treatment. Tolerability of the treatment with the SQ(®) grass SLIT-tablet and concomitant AIT were assessed by the physician and administration of AIT and adverse events (AEs) were recorded by the patients in diaries. AEs and adverse drug reactions (ADRs) were coded by using the Medical Dictionary for Regulatory Activities.In total, 181 patients were documented by 48 allergists and 160 patients treated with a concomitant AIT (SCIT 130, SLIT 30). AEs were reported in 58 (36.3 %) patients with concomitant AIT, and AEs considered related with the SQ(®) grass SLIT-tablet in 49 (30.6 %) and with concomitant AIT in 18 (11.3 %) patients. Treatment was discontinued due to ADRs in 12 (7.5 %) patients and severity of ADRs was assessed mild or moderate in 29 (18.1 %), and severe in 20 (12.5 %) patients. Most common reactions were localised at the application site of the SQ(®) grass SLIT-tablet as oral pruritus, throat irritation, oedema mouth and paraesthesia oral; no serious ADRs were reported. Overall tolerability of the SQ(®) grass SLIT-tablet if given with concomitant AIT was assessed as "good" or "very good" by 91.0 % of patients and 91.6 % of physicians.In comparison to data from previous studies no increase in frequency of AEs or change in the tolerability profile was observed when SLIT with the SQ(®) grass SLIT-tablet was administered with concomitant SCIT or SLIT.
| S-EPMC4782305 | biostudies-other
Project description:Epitope mapping of Der p 2, a clinically important dust-mite allergen is the first step in designing immunotherapy hypoallergen vaccine candidates. Twenty-one single alanine mutants of Der p 2 were generated and their secondary structure was analysed using circular dichroism spectra. Only one mutant, K96A resulted in a misfolded protein. All mutants were tested for serum IgE reactivity using serum from dust mite allergic individuals by immuno dot-blots. Mutations to five residues, N10, E25, K77, K96 and E102 consistently showed reduced IgE reactions compared to wild-type Der p 2, and therefore these residues constitute the major IgE epitopes of Der p 2. Two mutants with consistent low IgE binding, K96A and E102A, were subsequently evaluated as hypoallergen candidates. IgG antibodies raised in mice against both mutants could inhibit human IgE-binding to WT Der p 2. Both mutants had intact T-cell epitopes as they were able to stimulate peripheral blood mononuclear cell proliferation similar to WT Der p 2. However, a switch in Th1:Th2 cytokine profile was not observed. In summary, we have identified the major conformational epitopes of Der p 2, and evaluated two Der p 2 hypoallergen vaccine candidates for immunotherapy.
| S-EPMC5821840 | biostudies-other
Project description:Rationale: Oral immunotherapy (OIT) is an emerging treatment for food allergy. While desensitization is achieved in most subjects, many experience gastrointestinal symptoms and few develop eosinophilic gastrointestinal disease. It is unclear whether these subjects have subclinical gastrointestinal eosinophilia (GE) at baseline. We aimed to evaluate the presence of GE in subjects with food allergy before peanut OIT. Methods: We performed baseline esophagogastroduodenoscopies on 21 adults before undergoing peanut OIT. Subjects completed a detailed gastrointestinal symptom questionnaire. Endoscopic findings were assessed using the Eosinophilic Esophagitis (EoE) Endoscopic Reference Score (EREFS) and biopsies were obtained from the esophagus, gastric antrum, and duodenum. Esophageal biopsies were evaluated using the EoE Histologic Scoring System. Immunohistochemical staining for eosinophil peroxidase (EPX) was also performed. Hematoxylin and eosin and EPX stains of each biopsy were assessed for eosinophil density and EPX/mm2 was quantified using automated image analysis. Results: All subjects were asymptomatic. Pre-existing esophageal eosinophilia (>5 eosinophils per high-power field [eos/hpf]) was present in five participants (24%), three (14%) of whom had >15 eos/hpf associated with mild endoscopic findings (edema, linear furrowing, or rings; median EREFS = 0, IQR 0-0.25). Some subjects also demonstrated basal cell hyperplasia, dilated intercellular spaces, and lamina propria fibrosis. Increased eosinophils were noted in the gastric antrum (>12 eos/hpf) or duodenum (>26 eos/hpf) in 9 subjects (43%). EPX/mm2 correlated strongly with eosinophil counts (r = 0.71, p < 0.0001). Conclusions: Pre-existing GE is common in adults with IgE-mediated peanut allergy. Eosinophilic inflammation (EI) in these subjects may be accompanied by mild endoscopic and histologic findings. Longitudinal data collection during OIT is ongoing.
| S-EPMC6261984 | biostudies-literature
Project description:BackgroundThe distribution of Pooideae species varies across Europe. Especially, Timothy is less represented in Southern than in Northern Europe. Since allergenic cross-reactivity between pollens from different grasses is only partial, grass pollen-allergic patients are expected to display different sensitization profiles, with specific IgE directed against different combinations of allergenic epitopes, depending on their living places in Europe and the grasses they are exposed to. In this context, this study aimed at comparing two tablets commercially available for allergy immunotherapy, namely a 5-grass (Cocksfoot, Meadow-grass, Rye-grass, Sweet vernal-grass and Timothy) and a 1-grass (Timothy) pollen tablets, for their ability to represent the sensitization profiles of patients, depending on whether they live in Southern or Northern Europe.MethodsSera were collected from adult patients living in Spain (n?=?19) and Sweden (n?=?22). Tablets were compared for their ability to inhibit the binding of patient serum IgE to pollen allergens from twelve grasses commonly distributed throughout Europe, as determined by the areas under the curves obtained by ELISA-inhibition. Tablets were adjusted to an equivalent allergenic activity, based on the CBER/FDA bioequivalent allergy unit.ResultsInhibition of the IgE binding to pollen allergens from twelve grasses was significantly stronger with the 5-grass than with the 1-grass pollen tablet (p?<?0.0001), regardless of whether patients were considered as a whole or by geographical area. This difference between tablets was significantly greater for Southern than Northern European patients (p?<?0.05).ConclusionsCompared to the 1-grass tablet, the 5-grass tablet generally covers better the sensitization profiles of European patients, especially patients from Southern Europe, in principle less exposed to pollen from Timothy than from other grasses. The 5-grass tablet is therefore expected to elicit larger spectra of blocking antibodies, which might have implications in light of the generally accepted mechanisms of allergy immunotherapy.
| S-EPMC6391756 | biostudies-literature
Project description:IgE-mediated food allergies are caused by adverse immunologic responses to food proteins. Allergic reactions may present locally in different tissues such as skin, gastrointestinal and respiratory tract and may result is systemic life-threatening reactions. During the last decades, the prevalence of food allergies has significantly increased throughout the world, and considerable efforts have been made to develop curative therapies. Food allergen immunotherapy is a promising therapeutic approach for food allergies that is based on the administration of increasing doses of culprit food extracts, or purified, and sometime modified food allergens. Different routes of administration for food allergen immunotherapy including oral, sublingual, epicutaneous and subcutaneous regimens are being evaluated. Although a wealth of data from clinical food allergen immunotherapy trials has been obtained, a lack of consistency in assessed clinical and immunological outcome measures presents a major hurdle for evaluating these new treatments. Coordinated efforts are needed to establish standardized outcome measures to be applied in food allergy immunotherapy studies, allowing for better harmonization of data and setting the standards for the future research. Several immunological parameters have been measured in food allergen immunotherapy, including allergen-specific immunoglobulin levels, basophil activation, cytokines, and other soluble biomarkers, T cell and B cell responses and skin prick tests. In this review we discuss different immunological parameters and assess their applicability as potential outcome measures for food allergen immunotherapy that may be included in such a standardized set of outcome measures.
| S-EPMC7670865 | biostudies-literature
Project description:BackgroundOral food challenge (OFC) is useful for diagnosing food allergies and assessing tolerance, but severe reactions may occur during the procedure.ObjectiveTo characterize the frequency and severity of reactions during cow's milk (CM) OFCs.MethodsA cross-sectional study was conducted to analyze the outcome of cow's milk oral food challenges (CMOFCs) performed to confirm IgE-mediated CM allergy or to assess food tolerance. CM was given first as baked milk (BM), followed by whole CM if there was no prior reaction to BM. An OFC was considered positive if IgE-mediated symptoms developed up to 2 h after ingestion. Symptoms were described and variables including age at OFC, prior anaphylaxis, other atopic diseases, and skin test results were compared according to the OFC outcomes.ResultsA total of 266 CMOFCs were performed, including 159 patients with a median age of 6.3 years old. One hundred thirty-six tests were positive and 62 resulted in anaphylaxis. Thirty-nine anaphylactic reactions were observed up to 30 min after the first dose. Severe anaphylaxis (cardiovascular and/or neurological involvement) was reported in 5 tests. A second dose of epinephrine was required in 3 tests, and 1 presented a biphasic response. Younger patients had a higher risk of anaphylaxis during baked milk oral food challenge (BMOFC) (p = 0.009). The frequency of anaphylaxis was higher in patients submitted to BM (p = 0.009).ConclusionsAnaphylaxis is a known complication of CMOFCs even when there is no prior anaphylaxis or when conducted with baked products. This study reinforces the importance of conducting OFC in appropriate settings with a well-trained team.
| S-EPMC10209878 | biostudies-literature
Project description:BACKGROUND:The effect of sublingual Timothy grass immunotherapy tablet 2800 BAU (grass SLIT-T) has been evaluated in three North American trials in adults and children who have allergic rhinitis with or without conjunctivitis (AR/C). This paper examines the effects of grass SLIT-T in Canadians. METHODS:Data for grass-allergic Canadians in three randomized, placebo-controlled, double-blind trials were analyzed post hoc: 1) adults ≥18 y, grass-pollen season [GPS] 2009; 2) children 5- <18 y, 2009; and 3) adults 18-65 y and children 5- <18 y, GPS 2012. Data from the GPS 2009 trials were pooled to provide a more precise estimate of treatment effects than the individual studies would provide. In every trial, participants received once-daily grass SLIT-T or placebo approximately 12 weeks before and continuing throughout the GPS. Participants used daily electronic diaries to record AR/C symptoms and medication use for treatment of symptoms. The therapeutic effect of grass SLIT-T was measured as a total combined score (TCS = daily symptom score + daily medication score) averaged over the entire GPS. Safety was assessed by monitoring adverse events (AEs). RESULTS:In the three trials, 386 Canadian participants were randomized; the overall population had 2284 participants. Canadian participants treated with grass SLIT-T in the pooled adult-pediatric 2009 trials showed a 38% mean TCS reduction relative to placebo (-2.06 difference [95% CI: -3.72, -0.39]; 3.32 vs. 5.37). Participants treated with grass SLIT-T in the adult-pediatric 2012 trial showed a 37% median TCS reduction relative to placebo (-1.53 difference [95% CI: -2.1, -0.3]; 2.58 vs. 4.11). Similar efficacy findings were observed over the peak GPS. Approximately 90% of treatment-related AEs were mild or moderate in severity. Two Canadian participants had moderate systemic allergic reactions (skin, respiratory, abdominal symptoms) to grass SLIT-T; symptoms resolved within 1 hour without medical intervention or treatment. No serious or life-threatening treatment-related AEs occurred. CONCLUSION:The 2800 BAU Timothy grass SLIT-T significantly improved AR/C induced by Timothy grass pollen in adults and children ≥5 y in Canadians, which was consistent with the robust efficacy observed in the overall trial population. The treatment was generally well tolerated. TRIAL REGISTRATION:Clinicaltrials.gov identifiers NCT00562159, NCT00550550, NCT01385371.
| S-EPMC4326370 | biostudies-literature