Experimental Allergic Rhinitis Research Articles

Adjuvant alum regulates the eIF2a-GATA3 axis in CD4+ T cells to influence allergen immunotherapy.

Allergen-specific immunotherapy (AIT) is an aetiology-targeting therapy for allergic diseases. The therapeutic mechanism of AIT is not fully understood yet. Endoplasmic reticulum stress is associated with the pathogenesis of allergic disorders. This study aims to elucidate the effects of AIT on suppressing allergic response through regulating endoplasmic reticulum stress. In this study, patients with perennial allergic rhinitis were recruited. AIT was conducted for the patients. An allergic rhinitis (AR) mouse model was established with mite extracts as allergens. We found that AIT modulated the endoplasmic reticulum stress status in peripheral CD4+ T cells in patients with allergic rhinitis. The intensity of endoplasmic reticulum stress associated the PERK (protein kinase RNA-like endoplasmic reticulum kinase)-eIF2a (eukaryotic translation initiation factor 2a) axis in CD4+ T cells was upregulated by AIT, which was closely associated with the improvement in allergic rhinitis response after AIT. eIF2a interacted with GATA3 to downregulate the IL4 gene transcription in CD4+ T cells. High doses of aluminium hydroxide (alum) in AIT vaccines enhanced the activity of XBP1 to suppress eIF2a in CD4+ T cells. AIT containing a low dose of alum effectively mitigated the experimental allergic rhinitis, while the AIT without alum or a high dose of alum exacerbated the experimental allergic rhinitis. In conclusion, the alum adjuvant in allergen vaccines can regulate the activity of eIF2a to regulate the expression of Th2 cytokines in CD4+ T cells. Manipulating the alum dose in AIT vaccines has the potential to enhance the therapeutic effects of AIT.

Modulating endoplasmic reticulum stress attenuates mast cell degranulation

ObjectivesDegranulation of mast cells leads to direct allergic symptoms. The underlying mechanism needs to be explored further. Endoplasmic reticulum (ER) stress is involved in the pathogenesis of allergic conditions. The objective of this study is to gain a better understanding of the mechanism of mast cell degranulation. MethodsBone marrow derived mast cells and mast cells isolated from the airway tissues were prepared. The role of ER stress in mediating the release of mast cells was tested. RNA sequencing (RNAseq) was used to investigate the genetic activities of mast cells. ResultsOur observation showed that sensitization increased ER stress in mast cells. X-box-1 binding protein (XBP1) activity was linked to mast cell degranulation. Modulation of ER stress or XBP1 expression regulates the release of the mast cell mediator. XBP1 promoted the mediator release of mast cells by activating spleen tyrosine kinase (Syk). Activation of eukaryotic initiation factor 2a (eIF2a) inhibited XBP1 in mast cells. Semaphorin 3A was effective in preventing experimental allergic rhinitis (AR) due to its ability to suppress the release of mast cell mediators. ConclusionsER stress is associated with the mast cell degranulation. By inhibiting XBP1, the crucial molecule of ER stress, mast cell degranulation can be suppressed and experimental AR can be mitigated.

The Therapeutic Effect of Capsaicin and/or Steroids on Inflammation in an Experimental Allergic Rhinitis Model

The Therapeutic Effect of Capsaicin and/or Steroids on Inflammation in an Experimental Allergic Rhinitis Model

Involvements of Nrf2 and oxidative stress in the ozone-elicited exacerbation in an allergic rhinitis model

Objective and designAn experimental rat allergic rhinitis(AR) model was made to explore the effect of different concentrations of ozone exposure and evaluate the roles of nuclear factor erythroid 2-related factor 2(Nrf2) and oxidative stress in ozone exposure. MethodSprague-Dawley rats were sensitized with ovalbumin (OVA). Three groups of AR rats were exposed respectively to different concentrations of ozone for 2 h on 6 weeks. Nasal symptoms and OVA- specific Ig E in the serum were evaluated. The pathological changes in the nasal mucosa were examined. Malondialdehyde (MDA) level and activity of superoxide dismutase(SOD) and glutathione peroxidase (GSH-Px,GPX) in the nasal mucosa tissue were measured through a spectrophotometry-based method. Nrf2、Kelch-1ike ECH- associated protein-l (Keap1) proteins was measured by western blotting. GPX1、GPX2 mRNA were detected by quantitative real time-PCR(qRT-PCR). ResultsOur results showed that ozone exposure induced a significant increase of the number of sneezes, nasal rubs, amount of nasal secretion and OVA-sIgE in the serum of AR model. Ozone effected oxidative stress in different concentration. The content of MDA in AREH group was significantly higher than AR groups. The activities of SOD and GSH-Px in nasal mucosa showed different trends in different concentration groups. The activities of SOD and GSH-Px in AREL and AREM groups were higher than AR group, but decreased at AREH group. The nucleoprotein level of Nrf2 in AREL and AREM groups was higher than AR groups. However, in AREH group, it was significantly decreased, compared with AREL and AREM groups. GPX1 and GPX2 mRNA levels in nasal mucosa showed the same trend in different exposure groups. ConclusionsDifferent concentrations of ozone inhalation causes changes of the expression of Nrf2 nuclear protein and its target genes in nasal mucosa of AR. High concentration ozone breaks the redox balance and aggravates oxidative damage in AR. This study suggests that inhibiting oxidative stress might be a solution for ozone-elicited detrimental effects on AR.

The Role of Substance P Receptor Antagonists in Allergic Rhinitis: Ovalbumin-Induced Rat Model.

Substance P is a peptide from the tachykinin family, which is found in peripheral and central nervous systems, causing vasodilation and increased secretion in the nasal mucosa. In this study, we aimed to investigate whether the experimental model of allergic rhinitis will cause allergic changes in the larynx and to compare the effects of aprepitant, a substance P antagonist, on nasal symptoms in allergic rhinitis, and histopathological changes in the nasal and laryngeal mucosa with antihistamine and leukotriene receptor antagonists (LTRA). An experimental animal study. The study was carried out on 34 healthy 8-12 weeks old female Sprague Dawley rats in 5 groups. The rats in which an experimental allergic rhinitis model was created with ovalbumin were scored by observing their nasal symptoms, and nasal and laryngeal mucous membranes included in the study were evaluated histopathologically after medications. As a result of the analysis of the data obtained from the study, antihistamine and LTRA significantly reduced the symptoms of nose scratching and sneezing, while aprepitant did not affect nasal symptoms. In the histopathological examination of the larynx, effects that would make a significant difference were found in the allergy group when compared to the control group. On the larynx, aprepitant reduced pseudostratification significantly compared to the allergy group. Aprepitant provides histopathological changes in the treatment of allergic rhinitis, but does not have sufficient effect on nasal symptoms. The effect of aprepitant on the larynx has not been clearly demonstrated. NA Laryngoscope, 133:2891-2897, 2023.

Expression of Concern: Essential Contribution of CD4+ T Cells to Antigen-Induced Nasal Hyperresponsiveness in Experimental Allergic Rhinitis.

Expression of Concern: Essential Contribution of CD4+ T Cells to Antigen-Induced Nasal Hyperresponsiveness in Experimental Allergic Rhinitis.

TAFA4-IL-10 axis potentiate immunotherapy for airway allergy by induction of specific regulatory T cells

Allergen-specific immunotherapy (AIT) is the main treatment for allergic diseases. The therapeutic efficacy of AIT has to be improved. Neuropeptides, such as TAFA4, have immune-regulating features. The objective of this study is to promote the efficacy of AIT in experimental allergic rhinitis (AR) by the concurrent use of TAFA chemokine as a family member 4 (TAFA4). In this study, an AR mouse model was developed using ovalbumin (OVA) as the specific antigen. The AR response was assessed in mice after treatment with AIT or/and TAFA4. We found that exposure to TAFA4 activated dendritic cells (DCs) in the airway tissues. Activation of DC by TAFA4 resulted in the expression of IL-10. TAFA4 also promoted the activities of c-Maf inducing protein. The FPR1-MyD88-AKT signal pathway was associated with the TAFA4-induced Il10 expression in the DCs. Co-administration of AIT/TAFA4 attenuated the AR response in mice by inducing antigen-specific Tr1 cells. In conclusion, TAFA4 induces the expression of IL-10 in DCs. Acting as an adjuvant, TAFA4 significantly improves AIT’s therapeutic efficacy against AR by inducing antigen-specific Tr1 cells.

The effect of topical intranasal H89 and dimethylsulfoxide on AQP5 levels and histopathological findings in an experimental allergic rhinitis rat model

The effect of topical intranasal H89 and dimethylsulfoxide on AQP5 levels and histopathological findings in an experimental allergic rhinitis rat model

An eosinophil-Sos1-RAS axis licenses corticosteroid resistance in patients with allergic rhinitis

BackgroundCorticosteroid resistance (CR) is a serious disadvantage in treating many chronic inflammatory conditions. Eosinophils are the main inflammation cells in allergic reactions. Environmental pollution, such as PM2.5, is associated with the pathogenesis of allergic disorders. The objective of this study is to elucidate the mechanism by which the exposure to PM2.5 confers eosinophil CR status. MethodsPatients with allergic rhinitis were recruited and assigned to corticosteroid sensitive (CS) and CR groups. Eosinophils were purified from nasal lavage fluids collected from patients with allergic rhinitis. A murine AR mouse model was developed with dust mite allergens and PM2.5 as the sensitization reagents. ResultsCR status was detected in about 60% eosinophil collected in patients with AR. Upon exposure to eosinophil activators, CS eosinophils released a large quantity of mediators, which was suppressed by the presence of steroids in the culture. CR eosinophils demonstrated resistance to steroidal therapy. RAS activation levels in eosinophils were higher in CR eosinophils than in CS eosinophils. Higher expression of the Son of sevenless-1 (Sos1) was detected in CR eosinophils, which formed a complex with RAS and glucocorticoidreceptor-α in CR eosinophils to prevent the binding between steroids and glucocorticoidreceptor-α. The presence of an Sos1 inhibitor dissociated glucocorticoid receptor-α from RAS/Sos1 complex, that restored the sensitivity to steroids in eosinophils. Administering the Sos1 inhibitor effectively attenuated the experimental allergic rhinitis. ConclusionsCR status was detected in approximately 1/3 eosinophils sampled from patients with allergic rhinitis. Sos1 was instrumental in the development and perseverance of CR in eosinophils. Sos1 inhibition restored sensitivity to steroids in CR eosinophils, which effectively reduced experimental allergic rhinitis.

Glutaminolysis is required in maintaining immune regulatory functions in B cells.

IL-10-expressing regulatory B cells (B10 cells) are dysfunctional in patients with many immune disorders. The underlying mechanism remains to be further elucidated. Glutamine is an essential nutrient for cell metabolism. This study aims to elucidate the role of glutaminolysis in maintaining the immune regulatory capacity in B10 cells. Peripheral blood samples were collected from 50 patients with allergic rhinitis and 50 healthy control subjects. B cells were isolated from blood samples by cell sorting with flow cytometry. The role of glutaminolysis in regulating B10 cell activities was assessed by immunological and biochemical approaches. The results showed that B cells from patients with allergic rhinitis expressed low levels of the transporter of glutamine and neutral amino acid. Glutaminolysis was required in the IL-10 expression in B cells. The glutamine catabolism was required in B10 cell generation. The mTOR activation mediated the glutaminolysis-associated B10 cell induction, and the suppression of the B cell glycogen synthase kinase-3 (GSK3) activation. GSK3 activation suppressed IL-10 expression in B cells. Inhibition of GSK3 enhanced IL-10 expression in B cells and alleviated experimental allergic rhinitis by generating immune competent type 1 regulatory T cells.

MicroRNA-345-5p acts as an anti-inflammatory regulator in experimental allergic rhinitis via the TLR4/NF-κB pathway

Allergic rhinitis (AR) is a common chronic condition characterized by inflammation of the nasal mucosa. The correlation of microRNAs (miRNAs) in AR has been highlighted particularly due to their roles in regulating inflammatory responses. The aim of this study was to explore the anti-inflammatory mechanism by which miR-345-5p regulates the toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) pathway in mice with AR. Initially, the putative miR-345-5p binding sites on the 3′untranslated region of TLR4 was predicted and verified. AR models were established using ovalbumin, after which the functional role of miR-345-5p in AR was determined using gain- and loss-of-function approaches. We found that miR-345-5p was poorly expressed in nasal mucosal tissues of mice with AR. Meanwhile, TLR4 expression and the TLR4/NF-κB pathway were identified to be promoted, which were then suppressed in the presence of overexpressed miR-345-5p. In addition, nasal epithelial cell apoptosis and fibrosis were inhibited in response to miR-345-5p overexpression and TLR4 silencing. Furthermore, miR-345-5p overexpression and TLR4 silencing were observed to decrease Th2 cells, expression of pro-inflammatory factors, but to increase Th1 cells and expression of anti-inflammatory factors. This study demonstrates an important role of miR-345-5p in alleviating the inflammatory response in mice with AR by inhibiting the TLR4/NF-κB pathway. Therefore, a better understanding of this process may aid in the development of novel therapeutic agents of AR.

Potential synergistic effects of novel hematopoietic prostaglandin D synthase inhibitor TAS-205 and different types of anti-allergic medicine on nasal obstruction in a Guinea pig model of experimental allergic rhinitis

Nasal obstruction is one of the most bothersome symptoms of allergic rhinitis (AR) affecting sleep-related quality of life in AR patients. Although several treatments were tested to control nasal obstruction, some patients with moderate to severe AR do not respond to current treatments, including the combined administration of different types of anti-allergic medicine. Thus, new options for AR treatment are needed. This study aimed to evaluate the effects of combined treatment with a novel inhibitor of hematopoietic prostaglandin D synthase (HPGDS), TAS-205, and different types of anti-allergic medicine on nasal obstruction in AR. Firstly, we demonstrated that TAS-205 selectively inhibited prostaglandin D2 (PGD2) synthesis in an enzymatic assay in a cell-based assay and in vivo models of AR. Moreover, treatment with TAS-205 alone suppressed eosinophil infiltration into the nasal cavity and late phase nasal obstruction. The combined administration of TAS-205 with montelukast, a cysteinyl leukotriene receptor 1 antagonist, showed significant additive inhibitory effects on eosinophil infiltration and late phase nasal obstruction compared to treatment with each agent alone. In contrast, concomitant treatment with TAS-205 and fexofenadine, a histamine H1 blocker, showed inhibitory effects on late phase and early phase nasal obstruction, although the magnitude of the inhibitory effects upon combined administration was comparable to that of each single treatment. These results suggest that combined treatment with an HPGDS inhibitor and different types of anti-allergic medicine may be a promising strategy to control nasal obstruction in AR patients.

Effect of Biospray Dressings on Eosinophil Infiltration in the Nasal Mucosa and Serum IgE Levels After Nasal Provocation in Experimental Allergic Rhinitis.

PurposeTo investigate the effect of biospray dressing on the extent of eosinophil infiltration in the nasal mucosa and the level of serum IgE in experimental allergic rhinitis with nasal provocation.MethodTwenty-four BALB/c mice were randomly divided into the normal control group, allergic rhinitis (AR) group, dexamethasone (DEX) treatment group, and biospray dressing (BD) group. The mice in the latter 3 groups were prepared for animal models of AR according to standard protocols. Mice in the BD group were administered a nasal spray before the nasal provocation, and those in the DEX group were administered an intraperitoneal injection of DEX. The nasal mucosa and serum were collected from each group. Nasal mucosa eosinophil infiltration was evaluated using hematoxylin and eosin staining, and enzyme-linked immunosorbent assay (ELISA) was performed to analyze the serum IgE expression.ResultsEosinophil infiltration (AR vs BD P = .009) in the nasal mucosa and serum IgE expression (AR vs BD P = .001) were significantly lower in the BD group than in the AR group. There were no significant differences in the extent of eosinophil infiltration in the nasal mucosa or serum IgE expression between the BD and DEX groups.ConclusionBiospray dressings can significantly reduce allergen provocation in the nasal cavity and have a protective effect on the nasal mucosa. They can be used for the prevention and treatment of AR.

The effect of Oleuropein on liver in experimental allergic rhinitis model

The effect of Oleuropein on liver in experimental allergic rhinitis model

Soluble CD83 alleviates experimental allergic rhinitis through modulating antigen-specific Th2 cell property.

Background and aims: Dysfunction of the immune regulatory system plays a role in the pathogenesis of allergic rhinitis (AR). The underlying mechanism needs to be further investigated. Published data indicate that soluble CD83 (sCD83) has immune regulatory activities. This study aims to investigate the role of sCD83 in the alleviation of experimental AR.Methods: Peripheral blood samples were obtained from AR patients. Serum levels of sCD83 were determined by enzyme-linked immunosorbent assay. A murine AR model was developed to test the effects of sCD83 on suppressing experimental AR.Results: We found that serum levels of sCD83 in the AR group were lower than that in the healthy control group. A negative correlation was identified between the serum sCD83 levels and the frequency of T helper-2 (Th2) cells. The low serum sCD83 levels were also associated with the Bcl2L12 expression in antigen-specific Th2 cells. Exposure to sCD83 enhanced the responsiveness of antigen-specific Th2 cells to apoptosis inducers via suppressing the Bcl2L12 expression. Administration of sCD83 efficiently suppressed experimental AR.Conclusions: sCD83 contributes to immune homeostasis by regulating CD4+ T cell activities. Administration of sCD83 may have translational potential for the treatment of AR or other allergic diseases.

Nasal instillation of probiotic extracts inhibits experimental allergic rhinitis.

Aim:Allergic rhinitis (AR) is a common disease. The therapeutic efficacy of AR needs to be improved. This study aims to evaluate the effects of local administration of probiotic extracts on inhibiting experimental AR. Methods: Epithelial cells (ECs) were primed by exposing to Clostridium butyricum extracts (CBe) in the culture to upregulate the expression of IL-10. A mouse AR model was developed to assess the therapeutic potential of CBe in AR. Results: CBe markedly induced the expression of IL-10 in ECs. Co-culture of naive B cells with CBe-primed ECs significantly increased IL-10 expression in the B cells (iB10 cells). The iB10 cells showed immune suppressive function in suppressing effector CD4+ T-cell proliferation. Treatment with nasal drops containing CBe efficiently inhibited experimental AR in mice. Conclusion: Local administration of CBe can efficiently inhibit experimental AR.

Antiallergical Effect of New Combined Nazal Aerodisperse System in the Conditions of Experimental Allergic Rhinitis

To assess the severity of the anti-allergic effect of the combined nasal spray in the conditions of experimental allergic rhinitis. The experiment was performed on Balb / c male mice, which reproduced ovalbumin-induced allergic rhinitis. The test-spray composition of fexofenadine hydrochloride + ammonium glycyrrhizinate in doses of 2.5 μg; 5 μg and 7.5 μg / nostril and compartion drugs: beclomethasone («Nasobec», IVAX Pharmaceuticals) and levocabastine («Tyzine® Allergy», Johnson & Johnson) in doses of 3.5 μg / nostril and 5 μg / nostril respectively, were administered intranasally after 14-day immunization of animals. On the 17th day of the experiment, the severity of nasal symptoms (sneezing and nasal grooming), the change in the concentration of histamine, IFN-γ, IL-6, IgE, and TNF-α and markers of oxidative stress (superoxide dismutase activity and concentration of malonic dialdehyde) were determined. The use of levocabastine and beclomethasone contributed to the reduction of allergic symptoms, with the most pronounced pharmacological effect observed with the administration of beclomethasone. The administration of the 5 μg of test-spray reduced nasal symptoms in mice and also contributed to a decrease in the concentration of histamine, IFN-γ, IL-6, IgE, and TNF-α, as well as the restoration of pro / antioxidant balance. At the same time, the test aerodisperse system at a dose of 5 μg was comparable to beclomethasone and exceeded levocabastine in terms of pharmacological action. The high effectiveness of the test-spray, comparable to itranasal glucocorticoids, makes this compound a promising drug corrector of allergic rhinitis.

Using high-throughput metabolomics to discover perturbed metabolic pathways and biomarkers of allergic rhinitis as potential targets to reveal the effects and mechanism of geniposide.

In this study, we probed the molecular mechanisms of metabolic biomarkers and pathways affected by the bioactive ingredient geniposide (GP), which was shown to protect against experimental allergic rhinitis in mice. The methods used here involved a metabolomics strategy based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-TOF/MS). Using the metabolomics strategy, serum samples of mice in control, model and GP groups were used to explore the differential production of metabolites and pathways related to defense activity of GP towards allergic rhinitis. Allergic symptom, inflammatory factors, and cell populations in the mice spleens were reversed by GP treatment. Seventeen potential biomarkers were discovered in experimental allergic rhinitis mice. GP was shown to have a regulatory effect on 12 of them, which were associated with 8 key metabolic pathways. The ingenuity pathway analysis platform was used to further understand the relationship between metabolic changes and pharmacological activity of GP. The pathways which affected by GP involved cellular growth and proliferation, organismal development, and free radical scavenging. This metabolomics study produced valuable information about potential biomarkers and pathways affected by GP during its effective prevention and therapeutic targeting of allergic rhinitis.

Anti-allergic and anti-inflammatory effects of the Bcl-2 inhibitor ABT-737 on experimental allergic rhinitis models

The anti-cancer agent ABT-737 is designed specifically to inhibit anti-apoptotic proteins of the Bcl-2 family. The development of cancer has long been associated with inflammation. Here, we assess the anti-allergic and anti-inflammatory effects and the underlying molecular mechanisms of ABT-737 on allergic rhinitis (AR) using in vitro and in vivo models. In the in vitro model, the ABT-737 treatment diminished the levels of several inflammatory cytokines in this case vascular endothelial growth factor (VEGF), thymic stromal lymphopoietin (TSLP), interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) by inhibiting caspase-1 and NF-κB activation in an activated human mast cell line, here HMC-1 cells. These mechanistic observations were validated in ovalbumin-sensitized AR mice. In an AR animal model, ABT-737 significantly diminished clinical symptoms of AR and the levels of AR biomarkers, specifically IgE, histamine, hypoxia-inducible factor-1α, VEGF, TSLP, IL-1β, IL-4, IL-5, IL-6, IL-13, TNF-α, intercellular adhesion molecule-1, and macrophage inflammatory protein-2. In addition, ABT-737 reduced the degree of caspase-1 activity compared to that in AR mice. Simultaneously, ABT-737 diminished the recruitment of mast cells and eosinophils into nasal mucosa tissues compared to the levels in AR mice. In conclusion, we identified new anti-allergic and anti-inflammatory effects of ABT-737. These results imply that ABT-737 can ameliorate allergic inflammatory diseases such as AR.

Effects of a Thermosensitive In Situ Gel Containing Mometasone Furoate on a Rat Allergic Rhinitis Model.

Background Mometasone furoate, one of the second generation intranasal corticosteroids, is currently used in suspension form due to its poor solubility. However, this is not favorable for nasal application because of the rapid elimination of the instilled drug from the nasal cavity by mucociliary clearance and delayed onset of action due to the slow dissolution of drug in suspension. Objective The aim of this study was to determine the antiallergic effects of mucoadhesive thermosensitive in situ gel containing mometasone furoate that we developed previously to prolong the contact between the drug and nasal mucosa and to prevent drainage of the formulation in an ovalbumin-induced rat model of allergic rhinitis. Methods An experimental allergic rhinitis model was developed in female Wistar albino rats by intraperitoneal injection of ovalbumin every 2 days for 14 days followed by its repeated intranasal instillation for 7 consecutive days. Intranasal instillation of ovalbumin was continued every other day for 14 days. Mometasone furoate in situ gel (5 μg/10 µl), mometasone furoate suspension (5 μg/10 µl), and physiological saline (10 µl) were administered into the bilateral nasal cavities from day 22 to day 35. Antiallergic effects were evaluated through histopathological evaluation, analysis of ovalbumin-specific serum immunoglobulin E, and a symptom score. Results Mometasone furoate in situ gel significantly decreased the nasal symptoms and ovalbumin-specific serum immunoglobulin E level as compared with mometasone furoate suspension and physiological saline. Additionally, inflammatory histological symptoms such as mucosal edema, vascular dilatation, eosinophil infiltration, and loss of cilia within the nasal mucosa of allergic rhinitis model rats were remarkably improved with the treatment of mometasone furoate in situ gel. Conclusion These results suggest that mometasone furoate in situ gel has a better therapeutic potential for the treatment of allergic rhinitis compared to mometasone furoate suspension.