The Hydrogel Based Allergen-Coated Gold Nanoparticles for Topical Administration: A Possible Epicutaneous Immunotherapy in Pollen-Sensitized Mice?

BACKGROUND: The rapid uptake of antigens by antigen-presenting cells (APCs) and their migration to draining lymph nodes in the initial hours after antigen administration in epicutaneous allergen specific immunotherapy (EPIT) prompted us to investigate whether the topical administration of allergens without patch application could alleviate allergy in pollen-sensitized mice. We evaluated the immunotherapeutic effect of topically administering hydrogel-based Gold nanoparticles (AuNPs) loaded with a total extract of Platanus orientalis pollen (Pla. ext (50 µg)-AuNPs) on intact skin. METHODS: Mice sensitized to P. orientalis pollen were divided into three groups and treated with Pla. ext (50 µg)-AuNPs: 1) patch with Pla. ext (50 µg)-AuNPs, 2) patch with Pla. ext (50 µg)-AuNPs in combination with hydrogel, and 3) topical application of Pla. ext (50 µg)-AuNPs in combination with hydrogel. The immunotherapeutic effects were evaluated by measuring serum specific and total IgE antibodies, total cell and eosinophil count in nasopharyngeal lavage fluid, cytokines in the supernatants of re-stimulated splenocytes by the total extract, and histological examination of lung and nasal mucosa. RESULTS: Topical administration of Pla. ext (50 µg)-AuNPs, like patch-based administration, significantly downregulated specific and total IgE and IL-4 production, promoted secretion of IFN-γ and IL-10, markedly reduced the number of inflammatory cells, particularly eosinophils, in nasopharyngeal lavage fluid (p < .05), and inhibited inflammation and pathological damage in lung and nasal mucosa. CONCLUSION: Our results suggest that topical administration of AuNPs loaded with P. orientalis total pollen extract on intact skin could be a potential application for EPIT in the P. orientalis pollen -sensitized mice.

The Art of Dosing for Subcutaneous Immunotherapy in North America.

Subcutaneous immunotherapy (SCIT) is a long-established treatment option for allergic rhinoconjunctivitis. Proper dosing of the allergens is critical for the efficacy and safety of SCIT. Of the hundreds of liquid allergen extracts in the United States, effective and well-tolerated SCIT dosing has only been established for a small number. Thus, SCIT dosing remains largely empiric and continues to be, by necessity, an art. To highlight the complexity of SCIT dosing, this review summarizes the historical and current landscape of U.S. allergen extracts, differences among U.S. and European allergen extracts, allergen selection for SCIT, considerations for compounding of allergen extract mixtures, and recommended dosing. As of 2021, 18 standardized allergen extracts are available in the United States; all other extracts remain unstandardized without characterization of allergen content or potency. U.S. allergen extracts differ from European extracts in formulation and potency characterization. There is no standardized methodology for SCIT allergen selection, and interpretation of allergen sensitization is not straightforward. Compounding of SCIT mixtures requires consideration of potential dilution effects, allergen cross-reactivity, proteolytic activity, and additives. Probable effective dose ranges for SCIT are recommended in U.S. allergy immunotherapy practice parameters, although there are few studies using U.S. extracts supporting these doses as therapeutic. In contrast, optimized doses of sublingual immunotherapy tablets have been confirmed in North American phase 3 trials. The SCIT dosing for each patient remains an art that requires clinical experience and consideration of polysensitization, tolerability, compounding of allergen extract mixtures, and the range of recommended doses within the context of extract potency variability.

Characteristics of adverse reactions due to subcutaneous allergen immunotherapy applied between 2011-2021: Single center experience.

Introduction: The aim of this study was to elucidate the incidence of local, large local and systemic reactions after subcutaneus immunotherapy (SCIT) injections in our clinic and to determine the characteristic features of these adverse reactions. Materials and Methods: A total of 6000 SCIT injections administered to 163 patients between January 2011 and December 2021 were retrospectively evaluated. The study population consisted of patients with allergic rhinoconjunctivitis who underwent SCIT due to pollen, house dust mite or cat allergy, or patients who underwent SCIT due to venom allergy. Demographic characteristics of the patients, diagnoses, allergen sensitivities, immunotherapy protocol applied, adverse reactions, and the characteristics of these reactions were recorded. Result: Totally, 163 patients with a mean age of 36.8 ± 12.7 years were enrolled in this research. Sex distribution was as follows: 55.2% (n= 90) were females. During the study, 218 allergic reactions were detected in 83 patients. The incidence of adverse reactions per injection was 3.6%. The probability of developing an adverse reaction in a patient during the entire subcutaneous immunotherapy was 53.9%. Of the adverse reactions that developed, 94 (43.1%, n= 47) were observed locally while 56 (25.7%, n= 40) were large local reactions, and 68 (31.2%, n= 30) were systemic. Incidence of adverse reactions per injection were 1.5%, 0.9%, and 1.1% for local reaction, large local reaction, and systemic reaction, respectively. Conclusions: The results of this analysis elaborated that subcutaneous immunotherapy is a safe and tolerable treatment modality. However, before initiating treatment, the benefits and risks should be evaluated. The risk of systemic reactions is quite low, but fatal anaphylaxis can occur, so physicians need to be aware of the potential risks.

Nasal and blood transcriptomic pathways underpinning the clinical response to grass pollen immunotherapy.

BACKGROUND: Allergen immunotherapy (AIT) is a well-established disease-modifying therapy for allergic rhinitis, yet the fundamental mechanisms underlying its clinical effect remain inadequately understood. Gauging Response in Allergic Rhinitis to Sublingual and Subcutaneous Immunotherapy was a randomized, double-blind, placebo-controlled trial of individuals allergic to timothy grass who received 2 years of placebo (n = 30), subcutaneous immunotherapy (SCIT) (n = 27), or sublingual immunotherapy (SLIT) (n = 27) and were then followed for 1 additional year. OBJECTIVE: We used yearly biospecimens from the Gauging Response in Allergic Rhinitis to Sublingual and Subcutaneous Immunotherapy study to identify molecular mechanisms of response. METHODS: We used longitudinal transcriptomic profiling of nasal brush and PBMC samples after allergen provocation to uncover airway and systemic expression pathways mediating responsiveness to AIT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01335139, EudraCT Number: 2010-023536-16. RESULTS: SCIT and SLIT demonstrated similar changes in gene module expression over time. In nasal samples, alterations included downregulation of pathways of mucus hypersecretion, leukocyte migration/activation, and endoplasmic reticulum stress (log2 fold changes -0.133 to -0.640, false discovery rates [FDRs] <0.05). We observed upregulation of modules related to epithelial development, junction formation, and lipid metabolism (log2 fold changes 0.104 to 0.393, FDRs <0.05). In PBMCs, modules related to cellular stress response and type 2 cytokine signaling were reduced by immunotherapy (log2 fold changes -0.611 to -0.828, FDRs <0.05). Expression of these modules was also significantly associated with both Total Nasal Symptom Score and peak nasal inspiratory flow, indicating important links between treatment, module expression, and allergen response. CONCLUSIONS: Our results identify specific molecular responses of the nasal airway impacting barrier function, leukocyte migration activation, and mucus secretion that are affected by both SCIT and SLIT, offering potential targets to guide novel strategies for AIT.

Lack of Harmonized Adherence Criteria in Allergen Immunotherapy Prevents Comparison of Dosing and Application Strategies: A Scoping Review.

Allergen immunotherapy (AIT) involves the application of increasing doses of allergen extract (as oral, sublingual, or subcutaneous immunotherapy) until immunologic tolerance is reached. Successful AIT relies on the consistent administration of allergen extract; therefore, adherence to these treatments is vital for compelling long-term results. Our review discusses the current terminology from adherence research in general, summarizes 25 current studies on adherence research in AIT in a scoping literature review, and delineates recommendations for tools and parameters for adherence research, aiming to improve outcomes in AIT. Almost every adherence study in AIT published to date used different tools, parameters, and data sources for measuring adherence and persistence rates. Unfortunately, an easily accessible, objective parameter or biomarker for monitoring treatment adherence and success has not yet been established for AIT. This situation calls for the development of an international core outcomes set for AIT that defines what is exactly meant by AIT adherence and how AIT adherence should be consistently measured. Therefore, we exemplarily present results and conclusions from adherence research in chronic diseases other than allergology. We aim to facilitate the development of advanced methods, considering the challenging disease specificities of these parameters in a routine care setting of AIT.

Cost-effectiveness analysis of grass pollen specific immunotherapy in children with allergic rhinitis compared to the standard of care symptomatic treatment in Portugal.

Summary: Background. Cost-effectiveness studies evaluating allergen immunotherapy (AIT) in children are scarce. We aim to compare the cost-effectiveness of subcutaneous (SCIT) and sublingual immunotherapy (SLIT) against standard-of-care (SOC) treatment in children with grass pollen allergic rhinitis. Methods. We created a Markov model to compare the three strategies over a 10-year horizon. SOC was the reference to calculate the incremental cost-effectiveness ratio (ICER). Deterministic and probabilistic sensitivity analysis were used to assess models' uncertainty. Results. We obtained an ICER of € 12,605 and € 6,318 for SLIT and SCIT, respectively. In sensitivity analysis, SCIT was more cost-effective than SLIT. Conclusions. AIT is cost-effective in children with grass pollen allergic rhinitis, especially for the subcutaneous route.

Efficacy and safety of sublingual versus subcutaneous immunotherapy in children with allergic rhinitis: a systematic review and meta-analysis.

Aim: To systematically compare the efficacy and safety of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) in children with allergic rhinitis (AR). Methods: PubMed, Embase, Cochrane Library, and Web of Science were searched from inception to March 2, 2023. Outcomes included symptom scores (SSs), medication scores (MSs), symptom and medication scores (SMSs), new sensitizations, development of asthma, improvement, and treatment-related adverse events (TRAEs). The quality of the included studies was assessed by the modified Jadad scale and Newcastle-Ottawa scale (NOS). Meta-regression was carried out to explore the source of heterogeneity. Subgroup analysis was further conducted in terms of study design [randomized controlled trials (RCTs), cohort studies], allergen [house dust mites (HDMs), grass pollen], treatment duration (≥ 24, 12-23 or < 12 months), allergen immunotherapy (AIT) modality (drops or tablets), and AIT protocol [continuous, pre-seasonal, co-seasonal, or after the grass pollen season (GPS)]. Sensitivity analysis was conducted for all outcomes. A Bayesian framework and a Monte Carlo Markov Chain (MCMC) model were developed for indirect comparison. Results: Totally 50 studies with 10813 AR children were included, with 4122 treated with SLIT, 1852 treated with SCIT, and 4839 treated with non-SLIT or non-SCIT therapy. For direct comparison, the SLIT group had a similar SS to the SCIT group [pooled standardized mean difference (SMD): 0.41, 95% confidence interval (CI): -0.46, 1.28, P = 0.353]. Comparable MSs were observed in the SLIT and SCIT groups (pooled SMD: 0.82, 95%CI: -0.88, 2.53, P = 0.344). For indirect comparison, no significant differences were found in SSs (pooled SMD: 1.20, 95% credibility interval (CrI): -1.70, 4.10), MSs (pooled SMD: 0.57, 95%CrI: -1.20, 2.30), SMSs (pooled SMD: 1.80, 95%CrI: -0.005, 3.60), new sensitizations [pooled relative risk (RR): 0.34, 95%CrI: 0.03, 3.58], and development of asthma (pooled RR: 0.68, 95%CrI: 0.01, 26.33) between the SLIT and SCIT groups; the SLIT group illustrated a significantly lower incidence of TRAEs than the SCIT group (pooled RR: 0.17, 95%CrI: 0.11, 0.26). Conclusion: Considering both efficacy and safety, SLIT might be a more favorable AIT than SCIT in the treatment of pediatric AR, which may serve as a decision-making reference for clinicians. Systematic review registration: PROSPERO (CRD42023460693).

A Comprehensive Overview of Allergen-specific Immunotherapy Types, Recombinant and Natural Extract Allergens in the Diagnosis and Treatment of Allergies.

Allergen-specific immunotherapy (AIT) involves administering allergen extracts. It is used to desensitize allergic patients. Herbal allergen extracts that are optimum in efficacy and fewest in side effects are still challenging to produce. To overcome these limitations, oral immunotherapy, epicutaneous immunotherapy, intralymphatic immunotherapy, and artificial recombinant allergen preparations have been evaluated. Recombinant allergens have become more popular with the development of molecular diagnostics and therapeutics. Besides food and drug allergens, pollen, fungal spores, and other allergens have been studied. Based on related clinical studies, this comprehensive overview will present the latest perspectives on AIT methods and available allergenic products, as well as discuss the challenges and opportunities for treating allergic disorders.

Safety of subcutaneous immunotherapy with carbamylated allergoids based on data from a pharmacovigilance database.

Aims: Allergen immunotherapy aims to induce tolerance, which persists after its discontinuation, to targeted allergens. However, concern exists regarding the use of subcutaneous immunotherapy with whole extracts due to frequently reported events of anaphylactic reactions. Materials & methods: In this pharmacovigilance study, the authors assessed the safety of subcutaneous immunotherapy with the monomeric allergoid Lais-in using a database of adverse reactions documented in real-world postmarketing reports from 2010 to 2020. Results & conclusion: The results showed that more than 171,916 doses of Lais-in were administered from 2010 to 2020, resulting in five adverse drug reactions. Nonserious adverse events, including hives, eye irritation and skin reactions, were reported. These data indicate that monomeric allergoids prevent serious reactions to subcutaneous immunotherapy.

Effectiveness and adverse reactions to subcutaneous immunotherapy in children with allergic rhinitis/asthma.

OBJECTIVE: Adverse reactions, which are mostly local and rarely systemic, can be seen during subcutaneous immunotherapy (SCIT). It was not possible to continue SCIT at times due to systemic reactions. The purpose of the present study was to identify the incidence and risk factors associated with adverse reactions during subcutaneous allergen-specific immunotherapy (AIT). METHODS: A total number of 344 patients under 18 years old with allergic rhinitis and/or asthma who underwent SCIT between 2005 and 2021 were included in the study. Demographic characteristics of the patients, laboratory findings [Total Immunglobulin E(IgE), aeroallergen prick test, inhaler, and allergen specific IgE(sIgE) and eosinophil counts], and adverse events observed during AIT were recorded retrospectively. Descriptive and univariate/multivariate logistic regression analyses were used to identify risk factors for adverse events. RESULTS: Among 344 patients, 33.4% (n = 115) were female, mean age was 133.1 ± 41.0 months, and 42.2% (n = 145) were >12 years old. One hundred-thirty eight (40.1%) of the patients were mono-sensitized, 47 (13.7%) had asthma, 207 (60.2%) allergic rhinitis, and 90 (26.2%) asthma and allergic rhinitis. Single allergen content was administered to 187 (54.4%) patients (62 mite, 114 grass mix, 11 olea), and multiple allergens to 157 (45.6%) patients (121 pollen mix, 36 other (mite/alternaria)]. A total number of 33.008 injections were administered. 840 adverse reactions (262 (31.1%) at up-dosing phase, 578 (68.8%) at maintenance phase) in 195 (56.7%) patients were observed. Among the adverse reactions, 632 (75.2%) were local, 160 (19%) large local, and 48 (5.7%) (39 at maintenance, 9 at up-dosing) (in 31 patients) were systemic (28 Grade 1, 12 Grade 2, 8 Grade 3). Adrenalin was administered to 8 patients with Grade 3 systemic reaction (8/33008; %0.024). Adverse reactions, especially local ones, were seen more frequently in children under 12 years old (p < 0.001). Patients sensitized with grass pollen (p:0.01) and mite (p:0.004), and those who had received SCIT with pollen mixture had more adverse reactions than the others. More adverse reactions were observed in SCIT containing calcium-phosphate as adjuvant (p: 0.01). Local reactions were risk factors for large local (OR = 3.591, %95 CI:2.064-6.247, p < 0.001) and systemic (OR = 2.190, %95 CI:1.005-4.722 p = 0.046) reactions at univariate analyses. Total nasal symptom scores, Visual Analog Scale and asthma symptom control test decreased after one year of treatment (p < 0.01). CONCLUSION: SCIT is a safe and effective treatment method in childhood that leads to improvements in all nasal symptoms and asthma after one year of treatment.

Adverse Events Associated with the Clinical Use of Bee Venom: A Review.

Bee venom is used to treat various diseases but can cause a tickling sensation and anaphylaxis during clinical treatment. Adverse events (AEs) associated with bee venom may vary depending on the dosage, method, route of administration, and the country, region, and user. We summarized the AEs of bee venom used in various ways, such as by the injection of extracts, venom immunotherapy (VIT), live bee stings, or external preparations. We conducted a search in eight databases up to 28 February 2022. It took one month to set the topic and about 2 weeks to set the search terms and the search formula. We conducted a search in advance on 21 February to see if there were omissions in the search terms and whether the search formula was correct. There were no restrictions on the language or bee venom method used and diseases treated. However, natural stings that were not used for treatment were excluded. A total of 105 studies were selected, of which 67, 26, 8, and 4 were on the injection of extracts, VIT, live bee stings, and external preparation, respectively. Sixty-three studies accurately described AEs, while 42 did not report AEs. Thirty-five randomized controlled trials (RCTs) were evaluated for the risk of bias, and most of the studies had low significance. A large-scale clinical RCT that evaluates results based on objective criteria is needed. Strict criteria are needed for the reporting of AEs associated with bee venom.

Standardized allergen extracts for allergen immunotherapy.

Nineteen U.S. allergen extracts were standardized by the U.S. Food and Drug Administration (FDA) between 1987 and 1998, including of two house-dust mites, short ragweed, cat hair and cat pelt, seven temperate and one southern grass, and six Hymenoptera venom preparations. Relevant literature was reviewed. For each allergen, a "representative" extract was established; the potency of each representative extract was determined by measurement of the total protein content (Hymenoptera venom), radial diffusion measurement of the dominant allergen (short ragweed and cat), or, if there was no dominant allergen, then by quantitative skin testing by using the ID50EAL (intradermal dilution for 50 mm sum of erythema determines the bioequivalent allergy units) method. In vitro tests were developed to allow the manufacturer to demonstrate that each lot of its extract was statistically identical, within defined limits, to the FDA reference extract. These tests included radial immunodiffusion, competitive enzyme-linked immunosorbent assay, and isoelectric focusing. The standardized extracts offer the advantage of consistent potency from lot to lot for each manufacturer and also from manufacturer to manufacturer, and assure the presence of recognized significant allergens within the extract. Therefore, standardized extracts offer improved safety and efficacy over their nonstandardized predecessors.

Case Report: Safe and Effective Sublingual Birch Allergen Immunotherapy in Two HIV-Positive Patients.

Allergen-specific immunotherapy (AIT) is a safe, effective treatment for respiratory allergies (such as moderate-to-severe allergic rhinoconjunctivitis) that are not controlled by symptomatic medications. The indications and contraindications for AIT have been defined in international guidelines and consensus statements. However, some of these contraindications are not evidenced- based but have been deduced from the theoretical risk of an interaction between AIT disease-modifying effect and immune or inflammatory comorbidities. In the absence of clinical trial evidence, the accumulation of experience as case reports can narrow the spectrum of absolute contraindications. The majority of international guidelines list HIV infection as a contraindication to AIT. Here, we describe two cases of safe, effective sublingual birch pollen AIT in HIV-positive patients undergoing concomitant antiretroviral therapy. A 32-year-old female and a 63-year-old male sensitized to tree pollen and with clinically confirmed birch pollen allergy underwent pre- and co-seasonal sublingual birch pollen AIT for three and two pollen seasons, respectively. The therapy was associated with a marked reduction in the frequency and intensity of allergic symptoms, and the reduced use of (symptomatic) rescue medication. Mild, local, treatment-emergent adverse events were noted throughout the course of treatment but resolved spontaneously. No serious adverse events were reported. In particular, there were no obvious harmful effects on the patients' immune status or viral load. Hence, sublingual birch pollen AIT proved to be effective and safe in two HIV-positive patients.

Safety and Effectiveness of a Single Multiallergen Subcutaneous Immunotherapy in Polyallergic Patients.

BACKGROUND: As the number of allergic sensitizations increases the severity of allergic respiratory diseases worsens. Multiple monoallergen immunotherapy can be accompanied by poor treatment adherence and high costs, single multiallergen immunotherapy needs to prove efficacy whilst maintaining a good safety profile. METHODS: Observational, retrospective, multicenter study using a 2-pollen single undiluted multiallergen subcutaneous immunotherapy (SCIT) in routine clinical practice in Spain. Patients with rhinoconjunctivitis, with/without controlled asthma, sensitized to grass, olive, Parietaria, Cupressus, plane tree and/or Salsola pollen were included. Primary and secondary clinical efficacy endpoints were quality of life (mini Rhinitis Quality of Life Questionnaire (miniRQLQ)) and visual analogue scale (VAS) respectively. All adverse events were documented. RESULTS: Ten centers included 97 patients, median age 32 years. SCIT treatment included combinations of grass mix with olive, Parietaria, Cupressus, plane tree or Salsola or olive with Parietaria, Cupressus or Salsola. The mean duration of SCIT was 1.8 years with a high treatment adherence (73%). Significant improvement in quality of life, nasal and ocular symptoms, activity limitations and practical problems (p< 0.0001) and other symptoms (p= 0.024) was observed. Most patients did not develop asthma-like symptoms and a significant improvement of all allergic symptom severity was perceived. VAS showed a significant improvement in rhinoconjunctivitis and asthma by patients and physicians. Twenty-nine patients experienced adverse reactions, 25 had local and 6 had systemic reactions. CONCLUSIONS: Single undiluted multiallergen SCIT treatment of two different pollens is efficacious and safe in both children and adults, showing that it is a suitable option for the treatment of polyallergic patients.

Nucleic acid vaccines and CpG oligodeoxynucleotides for allergen immunotherapy.

PURPOSE OF REVIEW: Molecular forms of allergen-specific immunotherapy (AIT) are continuously emerging to improve the efficacy of the treatment, to shorten the duration of protocols and to prevent any side effects. The present review covers the recent progress in the development of AIT based on nucleic acid encoding allergens or CpG oligodeoxynucleotides (CpG-ODN). RECENT FINDINGS: Therapeutic vaccinations with plasmid deoxyribonucleic acid (DNA) encoding major shrimp Met e 1 or insect For t 2 allergen were effective for the treatment of food or insect bite allergy in respective animal models. DNA expressing hypoallergenic shrimp tropomyosin activated Foxp3+ T regulatory (Treg) cells whereas DNA encoding For t 2 down-regulated the expression of pruritus-inducing IL-31. Co-administrations of major cat allergen Fel d 1 with high doses of CpG-ODN reduced Th2 airway inflammation through tolerance induction mediated by GATA3+ Foxp3hi Treg cells as well as early anti-inflammatory TNF/TNFR2 signaling cascade. Non-canonical CpG-ODN derived from Cryptococcus neoformans as well as methylated CpG sites present in the genomic DNA from Bifidobacterium infantis mediated Th1 or Treg cell differentiation respectively. SUMMARY: Recent studies on plasmid DNA encoding allergens evidenced their therapeutic potential for the treatment of food allergy and atopic dermatitis. Unmethylated or methylated CpG-ODNs were shown to activate dose-dependent Treg/Th1 responses. Large clinical trials need to be conducted to confirm these promising preclinical data. Moreover, tremendous success of messenger ribonucleic acid (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 must encourage as well the re-exploration of mRNA vaccine platform for innovative AIT.

Reduced anaphylactic potential of denatured pullulan-conjugated Cry j 1.

Japanese Cedar (JC) pollinosis is the most common seasonal allergic rhinitis in Japan. Throughout the JC pollen season, patients suffer from the allergic symptoms, resulting in a reduction of quality of life. Allergy immunotherapy (AIT) is an established treatment option for a wide range of allergens that unlike symptomatic treatments (e.g. antihistamines) may provide sustained immune tolerance. However, AIT, especially subcutaneous immunotherapy (SCIT) has a fatal anaphylaxis risk due to the use of crude allergen extracts. Consequently, development of allergen derivatives with substantially reduced anaphylactic potential is desirable. An allergen derivative that showed reduced IgE-binding and anaphylactic potential was developed through conjugation of native Cry j 1 (n Cry j 1), a major JC allergen, to the polysaccharide pullulan followed by chemical but non-covalent denaturation. The resulting Cry j 1 allergen derivative, Dn p-Cry j 1, showed reduced IgE-binding and IgE-mediated effector cell activation in vitro using an ELISA competition assay and a mast cell activation model (EXiLE). Reduced anaphylactic potential of Dn p-Cry j 1 in vivo was demonstrated using the rat passive cutaneous anaphylaxis (PCA) assay. The difference in anaphylactic potential of Dn p-Cry j 1 compared to n Cry j 1 in wild-type rats was of the same magnitude as the difference seen in the anaphylaxis reactions obtained with n Cry j 1 in wild-type rats and mast-cell deficient rats, indicating a dramatic reduction in anaphylactic potential of Dn p-Cry j 1. These results indicate that Dn p-Cry j 1 is a promising candidate for next-generation JC AIT.

Strategies and Future Opportunities for the Prevention, Diagnosis, and Management of Cow Milk Allergy.

The prevalence of food allergy has increased over the last 20-30 years, including cow milk allergy (CMA) which is one of the most common causes of infant food allergy. International allergy experts met in 2019 to discuss broad topics in allergy prevention and management of CMA including current challenges and future opportunities. The highlights of the meeting combined with recently published developments are presented here. Primary prevention of CMA should start from pre-pregnancy with a focus on a healthy lifestyle and food diversity to ensure adequate transfer of inhibitory IgG- allergen immune complexes across the placenta especially in mothers with a history of allergic diseases and planned c-section delivery. For non-breastfed infants, there is controversy about the preventive role of partially hydrolyzed formulae (pHF) despite some evidence of health economic benefits among those with a family history of allergy. Clinical management of CMA consists of secondary prevention with a focus on the development of early oral tolerance. The use of extensive Hydrolysate Formulae (eHF) is the nutrition of choice for the majority of non-breastfed infants with CMA; potentially with pre-, probiotics and LCPUFA to support early oral tolerance induction. Future opportunities are, among others, pre- and probiotics supplementation for mothers and high-risk infants for the primary prevention of CMA. A controlled prospective study implementing a step-down milk formulae ladder with various degrees of hydrolysate is proposed for food challenges and early development of oral tolerance. This provides a more precise gradation of milk protein exposure than those currently recommended.

Recent development on the use of sublingual immunotherapy tablets for allergic rhinitis.

OBJECTIVE: Allergic rhinitis (AR) is an immunoglobulin (Ig) E-mediated inflammatory condition that causes sneezing, nasal congestion, rhinorrhea, and nasal itch. Although subcutaneous immunotherapy for the treatment of AR has been in use and well established as a treatment modality, sublingual immunotherapy (SLIT) is increasingly considered to be the safer and more convenient alternative. Thus, the objective of this review is to describe recent findings pertaining to the use of SLIT tablets (SLIT-T) for AR. DATA SOURCES: A database search (PubMed.gov) for articles published between January 1, 2017, and February 9, 2021, was conducted using the following key words: "allergic rhinitis," AND-ed "sublingual immunotherapy." Included were randomized placebo-controlled trials. Other experimental design studies were excluded. STUDY SELECTIONS: A total of 11 randomized placebo-controlled trials were selected for full-text review and included in the analysis. All studies investigated the use of SLIT on patients with seasonal AR (4 tree pollen, 1 grass pollen, and 1 Japanese cedar) or perennial AR (3 house dust mite). RESULTS: Our review of 7 recently published randomized placebo-controlled trials with 2348 subjects receiving SLIT reported increased efficacy, safety, supportive immunologic parameters (IgE and IgG4 pre- and posttreatment levels), and improved quality of life. All studies excluded subjects with overlapping seasonal or perennial allergens, a history of moderate-to-severe uncontrolled asthma, or reduced lung function. CONCLUSION: Our review highlights that SLIT is a safe and effective treatment that considerably reduces symptoms and medication requirements in AR and improves quality of life.