Sublingual immunotherapy for pediatric patients with mite allergies.

ABSTRACT: Sublingual immunotherapy (SLIT) has been increasingly used instead of subcutaneous immunotherapy. SLIT was initially approved for use among adults; however, it has become more widely accepted for children. Few studies have evaluated the effectiveness of SLIT in the treatment of dust mite allergies among children, including adverse effects. This study aimed to investigate the effectiveness of SLIT in children with dust mite allergies, as well as its adverse effects, at a pediatric general outpatient clinic.I analyzed the data of 181 patients aged 4 to 12 years who tested positive for mite antigen-specific immunoglobulin E, exhibited nasal and/or eye symptoms, and received Miticure. Symptoms were evaluated using the Japanese rhino-conjunctivitis quality of life (QOL) questionnaire no. 1. Wilcoxon tests were used to compare the pretreatment and post-treatment symptom scores. Adverse events were tallied, and Kaplan-Meier curves and Wilcoxon tests were used to assess the proportion of dropouts.The mean QOL score at the baseline was 2.17 (standard deviation [SD] 1.45). After 1 week, the mean symptom QOL score was 1.63 (SD 1.32); the lowest mean score was found in week 41 (0.48, SD 0.63). A significant decline in the occurrence of all symptoms, including sneezing, nasal discharge, nasal congestion, itchy eyes, and teary eyes, was observed. Adverse effects were observed in 76 (42.0%) patients; the most common adverse effect was itchy mouth.SLIT improves symptoms with minimal adverse effects in pediatric patients.

Airway IL-1ß associates with IL-5 production following dust mite allergen inhalation in humans.

BACKGROUND: Preclinical studies implicate interleukin (IL)-1ß as a key mediator of asthma and have shown the efficacy of IL-1 antagonism for treatment of allergic airway inflammation; human studies in this area are lacking. OBJECTIVES: Our aim was to study the relationship of airway IL-1ß to features of acute allergen-induced asthma exacerbation in humans. METHODS: Dust mite-allergic adults with mild asthma underwent inhalation challenge with Dermatophagoides farinae. Fractional exhaled nitric oxide (FeNO), induced sputum and peripheral blood samples were obtained pre- and 24 h post-challenge. Spirometry was performed before and throughout the challenge at 10-min intervals, and allergen responsiveness was defined by a 20% fall in Forced Expiratory Volume in 1 s (FEV1). Sputum samples were analyzed for inflammatory cells, cytokines and chemokines. Multiple linear regression was employed to test the association between sputum IL-1ß concentration and biomarkers of T helper type 2 (T2)-dominant inflammation. RESULTS: Fourteen volunteers underwent inhaled allergen challenge. Allergen responsive volunteers showed a greater positive change in IL-1ß in sputum following allergen challenge compared to non-responders. Higher pre-challenge sputum IL-1ß was associated with greater increase in sputum IL-5 (p = 0.004), sputum eosinophils (p = 0.001) and blood IL-5 (p = 0.003) following allergen challenge. Allergen-induced sputum IL-1ß production was significantly associated with sputum and blood IL-5 (p < 0.001 and p = 0.007, respectively), sputum IL-4 (p = 0.001), IL-13 (p = 0.026), eosinophils (p = 0.008) and FeNO (p = 0.03). CONCLUSIONS: The positive association between production of IL-1ß and biomarkers of T2 inflammation, particularly IL-5, in humans is consistent with work in animal models that demonstrates a link between IL-1ß and the pathophysiology of allergic asthma. The role of IL-1ß in human asthma warrants further study.

Safety and effectiveness of the 300 IR sublingual house dust mite allergen immunotherapy tablet: 2-year interim analysis of a specified drug-use survey.

Background: The efficacy and safety of a house dust mite sublingual tablet (HDM-tab) have been demonstrated in clinical trials, but the findings must be confirmed in real-world use among more widespread patient populations. Materials & methods: A postmarketing drug-use survey is assessing the drug's safety and effectiveness during routine use for up to 4 years. This 2-year interim analysis reports data collected up to March 2020. Results: Of 545 registered outpatients, 526 were evaluable for safety and 371 for effectiveness. Most common adverse drug reactions were local reactions. Mean rhinitis severity score decreased from 2.5 ± 0.8 at baseline to 1.4 ± 0.9, 1.1 ± 0.8 and 1.0 ± 0.8 at 6 months, 1 year and 2 years, respectively. Conclusion: The HDM tab appears to be safe and effective in real-world conditions during 2 years of continuous use. Trial registration number: University hospital Medical Information Network (UMIN) Clinical Trials Registry identifier: UMIN000042840.

Dectin-1 Controls TSLP-Induced Th2 Response by Regulating STAT3, STAT6, and p50-RelB Activities in Dendritic Cells.

The epithelium-associated cytokine thymic stromal lymphopoietin (TSLP) can induce OX40L and CCL17 expression by myeloid dendritic cells (mDCs), which contributes to aberrant Th2-type immune responses. Herein, we report that such TSLP-induced Th2-type immune response can be effectively controlled by Dectin-1, a C-type lectin receptor expressed by mDCs. Dectin-1 stimulation induced STAT3 activation and decreased the transcriptional activity of p50-RelB, both of which resulted in reduced OX40L expression on TSLP-activated mDCs. Dectin-1 stimulation also suppressed TSLP-induced STAT6 activation, resulting in decreased expression of the Th2 chemoattractant CCL17. We further demonstrated that Dectin-1 activation was capable of suppressing ragweed allergen (Amb a 1)-specific Th2-type T cell response in allergy patients ex vivo and house dust mite allergen (Der p 1)-specific IgE response in non-human primates in vivo. Collectively, this study provides a molecular explanation of Dectin-1-mediated suppression of Th2-type inflammatory responses and suggests Dectin-1 as a target for controlling Th2-type inflammation.

Intralymphatic immunotherapy with tyrosine-adsorbed allergens: a double-blind, placebo-controlled trial.

BACKGROUND: Most previous studies used aluminum hydroxide-absorbed allergen extracts in evaluating the potential therapeutic roles of intralymphatic allergen-specific immunotherapy (ILAIT). In this study, we evaluated the therapeutic efficacy and safety of ILAIT with L-tyrosine-adsorbed allergen extracts of Dermatophagoides farinae, D. pteronyssinus, cat, dog, or mixtures thereof, in patients with allergic rhinitis induced by these allergens. METHODS: In this randomized, double-blind, placebo-controlled trial, study subjects received three intralymphatic injections of L-tyrosine-adsorbed allergen extracts (active group) or saline (placebo group) at 4-week intervals. RESULTS: Although ILAIT reduced daily medication use and skin reactivity to HDM and cat allergens at 4 months after treatment, overall symptom score on a visual analog scale (VAS), sinonasal outcome test-20 (SNOT-20), rhinoconjunctivitis quality of life questionnaire (RQLQ), daily symptom score (dSS), daily medication score (dMS), daily symptom medication score (dSMS), nasal reactivity to HDM allergen, and basophil activity to HDM, cat, and dog allergens at 4 months and 1 year after treatment were similar between the treatment and control groups. Intralymphatic injection was more painful than a venous puncture, and pain at the injection site was the most frequent local adverse event (12.8%); dyspnea and wheezing were the most common systemic adverse events (5.3%). CONCLUSIONS: ILAIT with L-tyrosine-adsorbed allergen extracts does not exhibit profound therapeutic efficacy in allergic rhinitis and can provoke moderate-to-severe systemic reactions and cause pain at the injection site. TRIAL REGISTRATION: clinicaltrials.gov: NCT02665754; date of registration: 28 January 2016.

Analysis of the long-term efficacy and safety of subcutaneous immunotherapy for atopic dermatitis.

Introduction: Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease characterized by severe pruritus and eczematous skin lesions. Subcutaneous immunotherapy (SCIT) refers to repeated contact with gradually increasing doses of allergen extracts, which improve patient tolerance to such allergens and controls, or reduces allergic symptoms. This study aimed to explore the long-term efficacy and safety of SCIT for patients with AD sensitized to house-dust mite (HDM). Methods: We conducted a retrospective analysis of 378 patients with HDM-sensitized AD. Among these patients, 164 received SCIT plus pharmacotherapy for 3 years (SCIT group) and the other 214 patients received only pharmacotherapy (non-SCIT group). The scoring atopic dermatitis (SCORAD) and pruritus visual analog scale (VAS) scores, laboratory test results, and adverse effects were recorded. Results: The SCORAD and pruritus VAS scores significantly decreased in the SCIT group. Also, the SCIT group showed higher reduction ratios of SCORAD and pruritus VAS scores than those observed in the non-SCIT group at 3 years after treatment initiation. The risk of development of new sensitization was higher in the non-SCIT group than in the SCIT group (relative risk 1.92 [95% confidence interval {CI}, 1.30-2.85]; p < 0.05). The eosinophil count of the participants significantly differed in the complete response (CR) group (p < 0.05) but not in the non-CR group (p = 0.098). However, the serum total immunoglobulin E value was not significantly reduced (p = 0.204). Of 8421 injections given to the patients, 231 injections (2.74%) showed adverse effects during the treatment period. Conclusion: Three years of SCIT can significantly reduce the severity and pruritus of moderate-to-severe AD with HDM sensitization. Patients who are multisensitized can also benefit from HDM SCIT. Patients can achieve long-term effects, such as prevention of neoallergen sensitization and inhibition of the allergy march.

Evaluation of sensitization to the crude extract of Dermatophagoides farinae and its derived allergens, Der f 2 and Zen 1, in dogs with atopic dermatitis in Southern Brazil.

BACKGROUND: Atopic dermatitis is associated with the production of IgE antibodies against environmental allergens and allergens of the house dust miteDermatophagoides farinae are frequently implicated in the disease. OBJECTIVES: We aimed to observe the allergen-specific IgE against crudeD. farinae, Der f 2 and Zen 1 in dogs with atopic dermatitis and report if these dogs are in contact with material that could shelter mite allergens. METHODS: 100 dogs with clinical diagnosis of atopic dermatitis were included after exclusion of other forms of pruritic skin disease and dogs that already received specific or non-specific immunotherapy. These dogs were of different breeds and ages and they were presented at a veterinary teaching hospital and a private service of veterinary dermatology, both located in Curitiba, Southern Brazil. At the time of anamnesis, some questions were applied to know the possibility of these dogs having had contact with furniture and textile material which could shelter house dust mites. Sera samples were obtained and further analyzed by ELISA assay to measure serum IgE levels against these allergens with an established cut-off of 0.200 IgE optical density. RESULTS: The allergen-specific IgE positivity against crudeD. farinae (92 %) and Zen 1 (77 %) was higher than Der f 2 (56 %). There was a correlation in sensitization to crude D. farinae and Zen 1 that was not observed between crude D. farinae and Der f 2 and Der f 2 and Zen 1. The sensitization to D. farinae and its allergens was associated with an unrestricted exposition to furniture and textile material. CONCLUSION & CLINICAL RELEVANCE: dogs with atopic dermatitis are frequently sensitized to D. farinae and its allergens, Der f 2 and Zen 1, may be considered major allergens in these dogs. Zen 1 may be the main allergen responsible for the sensitization to crude D. farinae.

Aqueous intradermal low-dose house dust mite immunotherapy in tropical settings: a valid cost-effective approach for developing nations?

INTRODUCTION: Aqueous allergen injections, an effective and century-old technique, is considered a second-line approach in daily clinical practice. Inconveniences still surround conventional subcutaneous immunotherapy (SCIT) administration, such as a need for frequent injections, prolonged up-dosing schedules, elevated costs, and the unlikely possibility of a systemic reaction. The intradermal immunotherapy route (IDR) might favorably impact many of the aforementioned issues (Table 1). House dust mite (HDM) allergens are the main perennial sensitizers in the tropics, and as such, are solely employed in immunotherapy treatments. METHODS: We carried out a year-long real-life study in 25 perennial allergic rhinitis children, symptomatic on exposure to house dust, employing an intradermal low-dose allergen mix consisting of 50 ng of Dermatophagoides pteronyssinus/Dermatophagoides farinae and 120 ng of Blomia tropicalis, under a unique cost-wise protocol. Basal symptoms/signs and face Visual Analog Scale (fVAS) scores were recorded for 2 weeks and later compared with those registered throughout the 1-year treatment. Serum-specific IgG4 and IL-10 levels were employed in the assessment of the immune responses. RESULTS: Symptoms/signs and fVAS scores were significantly reduced from days 42 and 49, respectively, and remained so until treatment completion. Increases in specific IgG4's and IL-10 levels reflected significant immune responses. Injections were well tolerated and families reported improved health status (quality of life, QoL). CONCLUSIONS: A unique cost-effective immunotherapy alternative for deprived allergic communities in tropical settings is depicted; further research is needed.

Anti-Inflammatory Effects of Ellagic Acid on Keratinocytes via MAPK and STAT Pathways.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that is characterized by an impaired skin barrier and intense itchiness, which decreases the individual's quality of life. No fully effective therapeutic agents have prevailed for AD due to an insufficient grasp of the complex etiology. Ellagic acid (EA), a natural compound, has anti-inflammatory properties in chronic diseases. The effects of EA on AD have not yet been explored. The present study investigated the effects of EA on TNF-α/IFN-γ-stimulated HaCaT keratinocytes and house dust mite-induced AD-like skin lesions in NC/Nga mice. Treatment with EA suppressed inflammatory responses in keratinocytes by regulating critical inflammatory signaling pathways, such as mitogen-activated protein kinases and signal transducers and activators of transcription. In vivo studies using a DfE-induced AD mouse model showed the effects of EA administration through ameliorated skin lesions via decremented histological inflammatory reactions. These results suggest that EA could be a potential therapeutic alternative for the treatment of AD by inhibiting inflammatory signaling pathways.

Platelets Independently Recruit into Asthmatic Lungs and Models of Allergic Inflammation via CCR3.

Platelet activation and pulmonary recruitment occur in patients with asthma and in animal models of allergic asthma, in which leukocyte infiltration, airway remodeling, and hyperresponsiveness are suppressed by experimental platelet depletion. These observations suggest the importance of platelets to various characteristics of allergic disease, but the mechanisms of platelet migration and location are not understood. The aim of this study was to assess the mechanism of platelet recruitment to extravascular compartments of lungs from patients with asthma and after allergen challenge in mice sensitized to house dust mite (HDM) extract (contains the DerP1 [Dermatophagoides pteronyssinus extract peptidase 1] allergen); in addition, we assessed the role of chemokines in this process. Lung sections were immunohistochemically stained for CD42b+ platelets. Intravital microscopy in allergic mice was used to visualize platelets tagged with an anti-mouse CD49b-PE (phycoerythrin) antibody. Platelet-endothelial interactions were measured in response to HDM (DerP1) exposure in the presence of antagonists to CCR3, CCR4, and CXCR4. Extravascular CD42b+ platelets were detected in the epithelium and submucosa in bronchial biopsy specimens taken from subjects with steroid-naive mild asthma. Platelets were significantly raised in the lung parenchyma from patients with fatal asthma compared with postmortem control-lung tissue. Furthermore, in DerP1-sensitized mice, subsequent HDM exposure induced endothelial rolling, endothelial adhesion, and recruitment of platelets into airway walls, compared with sham-sensitized mice, via a CCR3-dependent mechanism in the absence of aggregation or interactions with leukocytes. Localization of singular, nonaggregated platelets occurs in lungs of patients with asthma. In allergic mice, platelet recruitment occurs via recognized vascular adhesive and migratory events, independently of leukocytes via a CCR3-dependent mechanism.

Early Response of Specific IgE can Predict Satisfaction with Sublingual Immunotherapy.

OBJECTIVE: To investigate predictive parameters at baseline and during the early response to sublingual immunotherapy (SLIT) for house dust mites in allergic rhinitis patients. STUDY DESIGN: Retrospective cohort study. METHODS: Patients were treated with SLIT for at least 3 years and serological tests performed at baseline and at 1-year follow-up to investigate predictive parameters. Satisfaction with SLIT, 4 nasal symptoms, and quality of life were evaluated before and after 3 years of SLIT. Sixty-one patients were enrolled and divided into two groups depending on their satisfaction after 3 years of SLIT: 43 were satisfied (70.5%) and 18 were not (29.5%). RESULTS: Immunological parameters at baseline did not differ significantly between the satisfactory and unsatisfactory groups. However, changes in both Dermatophagoides pteronyssinus (Dp)- and D. farinae (Df)-specific IgEs were significantly higher in the unsatisfactory group than in the satisfactory group during the early response to SLIT (P = .006 and P = .045, respectively). CONCLUSION: The changes in both Dp- and Df-specific IgE levels during early response may be indicators for favorable long-term treatment outcomes with SLIT. These results suggest that clinicians could measure these immunological parameters 1 year after Dp and Df SLIT to indicate potential responders versus nonresponders. LEVEL OF EVIDENCE: 2b Laryngoscope, 131:467-472, 2021.

[EFFICACY, SAFETY AND IMMUNOLOGICAL RESPONSE WITH SQ HOUSE DUST MITE SUBLINGUAL IMMUNOTHERAPY-TABLET BY BODY WEIGHT IN CHILDREN].

BACKGROUND: Sublingual immunotherapy-tablet (SLIT-tablet) treatment includes the same dose regardless of the patients' age or body weight. We investigated the efficacy, safety and immunological response of SQ house dust mite (HDM) SLIT-tablet treatment in relation to body weight in children. METHODS: Total combined rhinitis score (TCRS), adverse events (AEs), adverse drug reactions (ADRs) and immunological response (IgE, IgG4) were evaluated post hoc in three subgroups (body weight < 30kg, 30-44kg, ≥ 45kg) of patients from a clinical trial for Japanese children with HDM allergic rhinitis (JapicCTI-152953). RESULTS: No apparent differences in TCRS were observed between the three subgroups. No differences in the frequency or nature of AEs were detected between the subgroups but the incidence of ADRs was decreased in the lower body weight subgroup. The most common ADRs occurred locally in the oral cavity and were categorized as mild. The levels of HDM specific IgE and IgG4 were increased compared to baseline in all subgroups. CONCLUSION: There were no influences of body weight for efficacy, safety, and immunological response in treatment with SQ HDM SLIT-tablet. These results indicated that SLIT dosage in children is same as adults without any concern in safety.

Activated leukocyte cell adhesion molecule as a biomarker for disease severity and efficacy of sublingual immunotherapy in allergic rhinitis.

BACKGROUND: Activated leukocyte cell adhesion molecule (ALCAM) plays an important role in T cell activation and immune response, but the role of ALCAM in allergic rhinitis (AR) remains unclear. The objective of the current study was to validate serum ALCAM as a biomarker in assessing disease severity and predicting the efficacy of sublingual immunotherapy (SLIT) in AR patients. METHODS: We recruited 40 healthy controls (HC group), 38 mild AR patients (MAR group) and 80 moderate-severe AR patients (MSAR group) in this study. Serum levels of ALCAM were determined by ELISA, and the association between ALCAM levels and disease severity was evaluated. In the MSAR group, 68 patients underwent and finished 3-years of SLIT, and were divided into effective group and ineffective group, the relationship between ALCAM levels and efficacy of SLIT was exampled. RESULTS: ALCAM levels were elevated in the serum of AR patients in comparison with HC. Moreover, serum ALCAM concentrations were higher in MSAR group than in MAR group and HC group, and levels of ALCAM significantly correlated with AR total nasal symptom score (TNSS) (r = 0.330, P < 0.001), visual analogue scale (VAS) (r = 0.387, P < 0.001) and serum total IgE levels (r = 0.442, P < 0.001). In the effective group, the ALCAM levels were significantly lower than in the ineffective group. Receiver operating characteristic (ROC) curve exhibited good accuracy for predicting clinical efficacy of SLIT (area under the curve = 0.805, P < 0.001). CONCLUSIONS: The serum ALCAM maybe a novel biomarker for assessing disease severity and predicting clinical efficacy of SLIT in AR patients.

Allergen Stability and Immunological Reactivity during Co-dissolution and Incubation of House Dust Mite and Japanese Cedar Pollen SLIT-Tablets.

Japanese allergic subjects are commonly sensitized to both house dust mite (HDM) and Japanese cedar pollen (JCP) and combined treatment with sublingual immunotherapy (SLIT) tablets is desirable. However, mixing extracts of two non-homologous allergens may compromise allergen stability and affect the clinical outcome. Therefore, we investigated the stability of major allergens and total allergenic reactivity of HDM and JCP SLIT-tablets following dissolution in human saliva or artificial gastric juice. Two fast-dissolving freeze-dried SLIT-tablets were completely dissolved and incubated at 37 °C. Major allergen concentrations and total allergenic reactivity were measured. After mixing and co-incubation of HDM and JCP SLIT tablets in human saliva for 10 min at 37°C, there were no statistically significant changes in major allergen concentrations. In addition, no loss of allergenic reactivity of the mixed two SLIT-tablet solutions was seen. In contrast, complete loss of allergenic reactivity and detectable major allergen concentrations occurred when the two SLIT-tablets were dissolved and incubated in artificial gastric juice. These results demonstrate that HDM or JCP major allergens and the total allergenic reactivity of both SLIT-tablets measured here remain intact after dissolution and co-incubation in human saliva, supporting the possibility of a dual HDM and JCP SLIT-tablet administration regimen if clinically indicated. The complete loss of allergenic reactivity after incubation in artificial gastric juice can furthermore be taken to indicate that the immunological activity of the allergen extracts contained in the two SLIT-tablets is likely to be lost or severely compromised upon swallowing.

Adjuvanting Allergen Extracts for Sublingual Immunotherapy: Calcitriol Downregulates CXCL8 Production in Primary Sublingual Epithelial Cells.

Application of allergens onto the sublingual epithelium is used to desensitize allergic individuals, a treatment known as sublingual immunotherapy. However, the response of sublingual epithelial cells to house dust mite allergen and potential tolerance-promoting adjuvants such as Toll-like receptor (TLR) ligands and calcitriol has not been investigated. In order to study this, primary sublingual epithelial cells were isolated from dogs and cultured in vitro. After 24-h incubation with a Dermatophagoides farinae extract, a Dermatophagoides pteronyssinus extract, TLR2 ligands (FSL-1, heat-killed Listeria monocytogenes, Pam3CSK4), a TLR3 ligand (poly I:C), a TLR4 ligand [lipopolysaccharide (LPS)], and calcitriol (1,25-dihydroxyvitamin D3), viability of the cells was analyzed using an MTT test, and their secretion of interleukin 6 (IL-6), IL-10, CXCL8, and transforming growth factor ß1 (TGF-ß1) was measured by enzyme-linked immunosorbent assay. Additionally, to evaluate its potential effect as an adjuvant, sublingual epithelial cells were incubated with calcitriol in combination with a D. farinae extract followed by measurement of CXCL8 secretion. Furthermore, the effect of D. farinae and calcitriol on the transcriptome was assessed by RNA sequencing. The viability of the sublingual epithelial cells was significantly decreased by poly I:C, but not by the other stimuli. CXCL8 secretion was significantly increased by D. farinae extract and all TLR ligands apart from LPS. Calcitriol significantly decreased CXCL8 secretion, and coadministration with D. farinae extract reduced CXCL8 concentrations to levels seen in unstimulated sublingual epithelial cells. Although detectable, TGF-ß1 secretion could not be modulated by any of the stimuli. Interleukin 6 and IL-10 could not be detected at the protein or at the mRNA level. It can be concluded that a D. farinae extract and TLR ligands augment the secretion of the proinflammatory chemokine CXCL8, which might interfere with sublingual desensitization. On the other hand, CXCL8 secretion was reduced by coapplication of calcitriol and a D. farinae extract. Calcitriol therefore seems to be a suitable candidate to be used as adjuvant during sublingual immunotherapy.

Efficacy of transdermal immunotherapy with biodegradable microneedle patches in a murine asthma model.

BACKGROUND: House dust mite (HDM) is a well-known cause of asthma. Allergen-specific immunotherapy (AIT) can only modify the natural course of the disease. Conventional routes of HDM AIT are subcutaneous or sublingual. Subcutaneous immunotherapy (SCIT) has a disadvantage of systemic hypersensitive reaction, and the sublingual immunotherapy has a disadvantage of local allergic reaction and low drug adherence. OBJECTIVE: To overcome the weak points of conventional AIT, we developed a HDM loaded biodegradable microneedle patch (MNP) for transdermal immunotherapy (TDIT). We aim to demonstrate the efficacy of TDIT in murine asthma model triggered by HDM compared with conventional SCIT. METHODS: To make HDM asthma mouse model, 5-week-old BALB/c female mice were sensitized and challenged by intranasal administration of HDM. The mice were divided into 5 groups: sham, asthma, low (10 µg) and high dose (100 µg) SCIT, and TDIT (10 µg). To make HDM loaded MNP, droplet-born air blowing method was used. Airway hyperresponsiveness and allergic inflammation markers were analysed by bronchoalveolar lavage fluid, immunohistochemistry, serum immunoglobulin (Ig) analysis, and lung cytokine assays. RESULTS: Airway hyperresponsiveness was ameliorated by TDIT. Eosinophilic inflammation in bronchoalveolar lavage was improved without adverse reactions. Reduction of Th2 (IL-4, IL-5, and IL-13) cytokines, and HDM-specific IgE, induction of Treg (IL-10, TGF-ß), Th1 (IFN-γ) cytokines were observed. Eosinophilic infiltration, goblet cell hyperplasia, and subepithelial fibrosis were also alleviated by TDIT. These changes were more significant in the TDIT group than in subcutaneous AIT group. CONCLUSION: In conclusion, HDM loaded biodegradable TDIT is a novel treatment option to treat asthma which showed more effectiveness and may have better safety profiles than conventional SCIT.

Association between biomarkers and house dust mite sublingual immunotherapy in allergic asthma.

BACKGROUND: House dust mite (HDM) sublingual immunotherapy (SLIT) has demonstrated efficacy in clinical trials of patients with asthma. Airway inflammation is a characteristic of respiratory allergy, but its relationship to SLIT remains unclear. OBJECTIVE: We evaluate the association between clinical outcomes with pulmonary function and biomarkers in before and after HDM SLIT (UMIN Number 000022390). METHODS: One hundred twelve patients with asthma sensitized to HDM were randomized to add-on 6 standardized quality (SQ)-HDM SLIT to pharmacotherapy or pharmacotherapy alone for 48 weeks. At baseline and end of study, biomarkers, blood eosinophils, serum IgE, serum periostin, fractional exhaled nitric oxide (FeNO), and spirometry and clinical symptoms were measured. Association between biomarkers and an increase in FEV1 of 120 mL or greater were analysed. RESULTS: Sublingual immunotherapy (SLIT) demonstrated a significant reduction of serum periostin (P < .001), FeNO (P < .01), and increase in HDM-specific IgE (P < .05), FEV1 (P < .001) and improvement of clinical symptom scores, when compared to pharmacotherapy. The change in FEV1 correlated with the changes in serum periostin (r = .696, P < .001) and the changes in FeNO (r = .682, P < .001). The independent predictor of improvement in airflow limitation was changed in serum periostin (r2  = .753, P = .013) and FeNO (P = .038). Based on cut-off values derived by receiver operating characteristic analysis (periostin 30.9 ng/mL, FeNO 28.0 ppb), patients were distinguished responders from non-responders, but with no predictive value for blood eosinophils or total IgE. The proportion of patients with both high periostin and FeNO levels was significantly higher in responder than in non-responder (P = .026). CONCLUSIONS AND CLINICAL RELEVANCE: Adding HDM SLIT to pharmacotherapy resulted in reduced serum periostin and FeNO, and improved pulmonary function. Serum periostin and FeNO may be useful biomarkers for prediction of SLIT.

Dust mite-derived Enterobacterial fimbriae H protein enforces the allergen specific immunotherapy in asthma mice.

BACKGROUND: The mite alimentary canal contains plenty of microbiota. It is accepted that some of the microbial products function as adjuvants to speed up immune responses. OBJECTIVES: We identified five bacterial proteins from dust mite, and Enterobacterial fimbriae H (FimH) was one of them. This study aims to test a hypothesis that the FimH protein enforces immunotherapy in asthmatic mice. METHODS: Asthmatic mice were treated by allergen specific immunotherapy (ASIT) with rDer f1/f2 or rDer f1/f2 plus FimH. Changes in inflammatory cell infiltration, airway hyperreactivity, frequency of Tregs, splenic CD4+IFN-γ+ cells, and serum levels of TGF-ß, IL-10, IL-13 and IL-17A of asthmatic mice were checked. RESULTS: ASIT with rDer f1/f2 plus FimH reduced inflammatory cell infiltration, airway hyperreactivity (AHR), and levels of IgE and IgG1 compared to ASIT with rDer f1/f2 alone, but the levels of IgG2a increased. Asthmatic mice that underwent ASIT with rDer f1/f2 plus FimH showed increased frequency of Tregs, splenic CD4+IFN-γ+ cells, serum levels of TGF-ß and IL-10; and deceased splenic CD4+IL-4+ cells, and serum levels of IL-13 and IL-17A. In vitro study showed FimH triggered IL-10 expression in a concentration dependent manner and facilitated the differentiation of Tregs. CONCLUSION: Used as an adjuvant, FimH enforces the effect of ASIT in asthmatic mice via augmenting Tregs.

[EVALUATION OF PROTOCOLS FOR RUSH SUBCUTANEOUS IMMUNOTHERAPY WITH STANDARDIZED HOUSE DUST MITE EXTRACTS].

BACKGROUND: Widely accepted loading protocols for rush subcutaneous immunotherapy (rSCIT) have not been established. Our aim was to evaluate the loading protocols of rSCIT. METHODS: In the low initial dose group (33 patients), the initial dose of standardized house dust mite extract was 1 JAU or less. The target dose at the end of the rush build-up phase was 500 JAU. Next, the initial dose was increased to 10 JAU with the same target dose in the high initial dose group (18 patients). Furthermore, in the modified high initial dosage group (17 patients), the initial dose was 10 JAU but the target dose at the end of the rush phase was 300 JAU. Then, the maintenance dose of 500 JAU was administered at 9 or 10 days after rSCIT initiation. We retrospectively evaluated these protocols. RESULTS: A systemic reaction (SR) occurred in 28 out of 33 (84.8%) patients in the low initial dosage group and in 12 out of 18 (66.7%) patients in the high initial dosage group, on the other hand significantly reduced in 4 out of 17 (23.5%) patients in the modified high-dosage group. The amount of antigen reached 339.3±19.0 JAU in the low initial dosage group and 358.3±24.9 JAU in the high initial dosage group at the end of the rush phase, significantly increased 452.9±20.6 JAU in the modified high-dosage group at 9 or 10 days. CONCLUSION: In rSCIT using standardized house dust mite extract, lowering the target dose at the end of the rush phase and delaying the administration of the maintenance dose may reduce SR and increase the reached amount of antigen.