Antigen-specific memory B cells play a key role in the induction of desensitization and remission to food allergens in oral immunotherapy and in the development of natural tolerance (NT). Here, we characterized milk allergen Bos d 9-specific B cells in oral allergen-specific immunotherapy (OIT) and in children spontaneously outgrowing cow's milk allergy (CMA) due to NT.

Samples from children with CMA who received oral OIT (before, during, and after), children who naturally outgrew CMA (NT), and healthy individuals were received from Stanford biobank. Bos d 9-specific B cells were isolated by flow cytometry and RNA-sequencing was performed. Protein profile of Bos d 9-specific B cells was analyzed by proximity extension assay.

Increased frequencies of circulating milk allergen Bos d 9-specific B cells were observed after OIT and NT. Milk-desensitized subjects showed the partial acquisition of phenotypic features of remission, suggesting that desensitization is an earlier stage of remission. Within these most significantly expressed genes, IL10RA and TGFB3 were highly expressed in desensitized OIT patients. In both the remission and desensitized groups, B cell activation-, Breg cells-, BCR signaling-, and differentiation-related genes were upregulated. In NT, pathways associated with innate immunity characteristics, development of marginal zone B cells, and a more established suppressor function of B cells prevail that may play a role in long-term tolerance. The analyses of immunoglobulin heavy chain genes in specific B cells demonstrated that IgG2 in desensitization, IgG1, IgA1, IgA2, IgG4, and IgD in remission, and IgD in NT were predominating. Secreted proteins from allergenspecific B cells revealed higher levels of regulatory cytokines, IL-10, and TGF-β after OIT and NT.

Allergen-specific B cells are essential elements in regulating food allergy towards remission in OIT-received and naturally resolved individuals.

Insect stings can cause large local reactions (LLRs) that are IgE-mediated and associated with considerable morbidity. A risk for systemic reactions including anaphylaxis to subsequent stings has been reported and is often noted by patients and health care providers. Guidelines do not recommend venom immunotherapy (VIT) for LLR based on the relatively low risk of anaphylaxis, but this is debated in this review. On the Pro side: the risk of anaphylaxis may be higher than reported in the limited literature, especially in patients who had only 1 LLR; new species with more potent stings are spreading into new areas; the quality of life can be markedly impaired by LLR; VIT is generally safe and highly effective. On the Con side: LLR are benign; stings occur infrequently; VIT has significant cost; systemic reactions occur more often to VIT than to stings in patients with LLR; FDA approval and published guidelines do not recommend VIT for LLR. In practice, shared decision-making is appropriate to incorporate knowledge of the natural history and known high-risk factors in the context of the patient's personal values and preferences.

The SQ tree sublingual immunotherapy (SLIT) tablet is authorised for treatment of allergic rhinoconjunctivitis with or without asthma in trees of the birch homologous group in 21 European countries. The primary objective of this study was to explore the safety in real-life.

In a prospective, non-interventional post authorisation safety study (EUPAS31470), adverse events (AEs) and adverse drug reactions (ADRs) at first administration and follow-up visits, symptoms, medication use, and pollen food syndrome were recorded by physicians in 6 European countries during the first 4-6 months of treatment.

ADRs with the SQ tree SLIT-tablet were reported in 57.7% of 1069 total patients (median age 36.0 years, 53.7% female) during the entire observation period (severity, mild-to moderate: 70.1%, severe: 4.7%, serious: 0.7%) and in 45.9% after first administration. ADRs were not increased with pollen exposure at first administration. With coadministration of the SQ tree and grass SLIT-tablet AEs were reported in 73.8% of patients and in 52.8% with the SQ tree SLIT-tablet alone. Nasal and eye symptoms improved in 86.9% and 80.9% of patients and use of symptomatic medication in 76.0%. PFS with symptoms was reported in 43.0% of patients at baseline and in 4.3% at the individual last visit.

The results of this non-interventional safety study with the SQ tree SLIT-tablet confirm the safety profile from placebo-controlled clinical trials and support effectiveness in real-life according to the published efficacy data. Safety was not impaired by pollen exposure at first administration or co administration with other SLIT-tablets.

IgE-mediated allergies represent a major health problem in the modern world. Apart from allergen-specific immunotherapy (AIT), the only disease-modifying treatment, researchers focus on biologics that target different key molecules such as allergens, IgE, or type 2 cytokines to ameliorate allergic symptoms. Singledomain antibodies, or nanobodies, are the newcomers in biotherapeutics, and their huge potential is being investigated in various research fields since their discovery 30 years ago. While they are dominantly applied for theranostics of cancer and treatment of infectious diseases, nanobodies have become increasingly substantial in allergology over the last decade. In this review, we discuss the prerequisites that we consider to be important for generating useful nanobody-based drug candidates for treating allergies. We further summarize the available research data on nanobodies used as allergen monitoring and detection probes and for therapeutic approaches. We reflect on the limitations that have to be addressed during the development process, such as in vivo half-life and immunogenicity. Finally, we speculate about novel application formats for allergy treatment that might be available in the future.

House dust mite (HDM) sensitisation can contribute to the development of allergic rhinoconjunctivitis (AR) or allergic asthma (AA). As treatment, allergen immunotherapy (AIT) is a promising approach, since it aims building immunotolerance against allergens, therewith establishing longterm efficacy. The evaluation of AIT has been investigated in many randomised controlled trials, whereas few real-world evidence studies are available.

We used data from the longitudinal prescription data base IQVIA LRx. Data on initial AIT prescriptions against HDM from January 2009 to December 2013 was analysed regarding treatment (subcutaneous AIT with either depigmented polymerised allergen extract [dSCIT] or other allergens [oSCIT], or sublingual immunotherapy [SLIT]) and treatment duration. Treatment groups were compared with a control group of AR patients not receiving AIT. Data on symptomatic medication was collected until February 2017 and progression of AR and AA was compared.

Data of 7260 patients with AIT prescriptions and of 21,780 control patients was analysed. AIT was associated with a significant decrease of AR medication intake compared with control (dSCIT: -34.0%, p < 0.0001; oSCIT: -25.7%, p < 0.0001; SLIT: -37.7%, p = 0.0026). In asthmatics, SCIT was associated with a significant decrease of asthma medication compared with control (dSCIT: -45.2%, p < 0.0001; oSCIT: -32.9%, p < 0.0001). Further, a significantly reduced likelihood for onset of asthma medication was demonstrated in patients treated with SCIT compared with controls (dSCIT OR: 0.759, p = 0.0476; oSCIT OR: 0.815, p = 0.0339).

Real-world data analyses indicate that AIT, particularly given via a subcutaneous route, reduces the need of medication against AR and AA and might delay the onset of asthma medication in patients with AR.

The 300IR house dust mite (HDM) sublingual immunotherapy (SLIT) tablet is approved for treatment of HDM-induced allergic rhinitis (AR). To provide a comprehensive review of the 300IR HDM-SLIT tablet safety profile based on randomized controlled trial (RCT) pooled data and postmarketing (PM) pharmacovigilance data.

Subjects (5-65 years) with confirmed HDM-AR with or without controlled asthma were treated with 300IR or placebo in 8 RCTs. Reported treatment-emergent adverse events (TEAEs) were pooled and analyzed descriptively in subsets of adults/adolescents and children. Adverse reactions (ADRs) collected from spontaneous reporting and PM studies through a pharmacovigilance system since the first marketing authorization were also analyzed.

Across RCTs, 1853 subjects were treated with the 300IR HDM-SLIT tablet and 1846 with placebo. In both subsets of adults/adolescents and children whichever their asthma status, treatment-related TEAEs of higher incidence in active groups vs placebo were mostly consistent with mild or moderate local application-site reactions. They were mainly reported on the first days of treatment and decreased over time. 4 severe laryngopharyngeal reactions (2 requiring adrenaline/epinephrine) and 1 moderate eczema considered serious rapidly resolved with medications; no anaphylaxis was reported. In PM settings, ADRs reported in more than 235,000 patients were in line with RCT findings. Severe systemic reactions occurred rarely; 12 anaphylactic reactions resolved safely (5 with adrenaline). No new safety signal was raised.

Safety data from RCTs and more than 7 years of real-life experience confirmed the favorable safety profile of 300IR HDM-SLIT tablet in patients across different regions, regardless of age and asthma status.

1) Peanut allergy is associated with high risk of anaphylaxis which could be prevented by oral immunotherapy. Patients eligible for immunotherapy are selected on the basis of a food challenge, although currently the assessment of antibodies against main peanut molecules (Ara h 1, 2, 3 and 6) is thought to be another option. 2) The current study assessed the relationship between the mentioned antibodies, challenge outcomes, skin tests and some other parameters in peanut-sensitized children. It involved 74 children, divided into two groups, based on their response to a food challenge. 3) Both groups differed in results of skin tests, levels of component specific antibodies and peanut exposure history. The antibody levels were then used to calculate thresholds for prediction of challenge results or symptom severity. While the antibody-based challenge prediction revealed statistical significance, it failed in cases of severe symptoms. Furthermore, no significant correlation was observed between antibody levels, symptom-eliciting doses and the risk of severe anaphylaxis. Although in some patients it could result from interference with IgG4, the latter would not be a universal explanation of this phenomenon. 4) Despite some limitations, antibody-based screening may be an alternative to the food challenge, although its clinical relevance still requires further studies.

Sublingual immunotherapy with Pru p3 extract (SLIT peach®) is used in allergy patients to multiple plant foods to induce tolerance to nonspecific lipid transfer proteins (nsLTP). The aim of this paper is to communicate the efficacy of a new ultrafast regimen. Until now on the initiation regimen lasts four days. We present a number of 22 patients with LTP-syndrome due to ingestion of different vegetable foods sensitized to Pru p3. According to European Academy of Allergy position paper (1) food immunotherapy is indicated when avoidance measures are ineffective, undesirable, or cause serious limitations on patients quality of life. Our patients had an impact on their quality of life (score > 130) before SLIT measured with (2) EuroPrevall Food Allergy Quality of Life Questionnaire (FAQLQ). The ultrafast regimen in one day is achieved in the 95% of our patients. Mild adverse reactions were observed, such as oral pruritus presence in almost all patients. Only one patient (5%) achieved the maintenance dose in two days due to intense oral pruritus. No patients presented systemic reactions. The maintenance dose achieved consists of 4 drops (0,16 ml) from vial number 4 daily. The concentration of Pru p3 in vial nº4 is 50 cg/ml. Four drops a day equals 8 micrograms of Pru p3. This new ultrafast regimen in one day is secure in patients with LTP Syndrome to induce tolerance to SLIT-peach® (Pru p3 extract).

Sublingual immunotherapy (SLIT) for perennial allergic rhinitis (AR) has not been extensively studied in preschoolers. We investigated the efficacy and safety of house dust mite (HDM) SLIT-tablet for children aged 1-4 years.

Children aged 1-4 years with AR were divided into SLIT (n = 22) and control (n = 12) groups based on their guardians' preferences. The SLIT group received a daily dose of 10,000 JAU of HDM SLIT tablet for 12 months, whereas the control group received symptomatic treatment only.

The baseline median age was 41 and 34 months in the SLIT and control groups, respectively, and the median AR symptom score was 4 for both groups. Compared with baseline, the AR symptom score had decreased significantly in the SLIT group after 12 months (score: 3, p = .002), whereas it tended to increase in the control group (score: 6, p = .08). Adverse reactions to SLIT were mild and occurred in eight patients (36%). In the SLIT group, Dermatophagoides (D.) farinae-specific IgE (sIgE) levels increased during the first 6 months and decreased to baseline levels at 12 months. In the control group, D. farinae-sIgE levels had increased significantly at 12 months compared to baseline (p = .01). D. farinae specific IgG4 and HDM IgE-blocking factor levels were significantly increased at 12 months compared to baseline in the SLIT group only (p < .001). A lower wheezing frequency was seen in the SLIT group (0.3%) compared to the control group (0.7%).

This pilot study demonstrated the efficacy, safety, and immunomodulatory effects of HDM SLIT-tablet in preschoolers with AR.