Murine Model Of Allergic Rhinitis Research Articles

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.

The environmental hormone nonylphenol interferes with the therapeutic effects of G protein-coupled estrogen receptor specific agonist G-1 on murine allergic rhinitis

The G protein-coupled estrogen receptor (GPER) specific agonist G-1 has therapeutic effects in patients with allergic diseases, but any role for G-1 as a therapy for inflammation associated with allergic rhinitis (AR) remains unclear. The structure of the environmental hormone nonylphenol (NP) is very similar to that of estrogen; it binds to the estrogen receptor to produce estrogen-like effects and thus may also bind to the membrane GPER. We explored whether NP administration would reduce the effects of G-1 on AR, the interactions between the two materials, and their mechanisms of action using a murine model of AR. Mice were randomly assigned into control, AR, G-1, and G-1 + NP groups (n = 10/group). AR nasal symptoms were scored. Eosinophils in nasal mucosa were counted after staining with hematoxylin and eosin. Serum ovalbumin (OVA)-specific IgE was determined by ELISA. The proportions of splenic Th1, Th2, and Treg cells were determined by flow cytometry. The expression of transcription factors unique to Th1, Th2, Treg cells and cytokine levels in nasal mucosa were evaluated by real-time PCR and cytometric bead arrays. AR nasal symptoms, including sneezing, nasal scratching, eosinophil infiltration of nasal mucosa, and serum IgE, were reduced in G-1 group. After injection, Th2 cells proportions, Th2-immune response-related cytokines (IL-4, IL-5, and IL-13), and a Th2 cell-specific transcription factor (GATA-3) were significantly decreased in G-1 group. Treg immune response was enhanced (as reflected by Treg cell, IL-10, and Foxp3 levels). The levels of all of these were significantly increased after adding NP, and the Treg immune response was significantly decreased. These results indicate that G-1 attenuated the nasal symptoms, serum OVA-specific IgE, and Th2 cell immune response, whereas it enhanced Treg immune response, in mice with AR. Adding NP weakened these therapeutic effects.

Effects of lentivirus-mediated CCR3 RNA interference on the function of mast cells of allergic rhinitis in mice

The CC chemokine receptor 3 (CCR3) expressed by eosinophils, mast cells and Th2 cells is closely related to allergic diseases. The objective of this study was to explore whether silencing of CCR3 with short hairpin RNAs (shRNAs) delivered by a lentiviral vector could impact the function of mast cells in a murine model of allergic rhinitis (AR) in vivo. The murine model of allergic rhinitis (AR) inducing by ovalbumin (OVA) was constructed, and the BALB/c mice were divided into normal control group, AR group, controlshRNA treated group and lentiviral CCR3-shRNA treated group. The recombinant lentivirus vectors which express a short hairpin RNA (shRNA) targeting the CCR3 were dropped into the nasal cavity of OVA-sensitized mice before the challenges. Real-time fluorescence quantitative PCR and western blotting were performed to observe inhibitory effect of CCR3 gene. Nasal symptoms of mice and OVA-specific IgE in each group were assessed. Concentrations of histamine, tryptase and Prostaglandin D2 (PGD2) in bone marrow, peripheral blood and nasal mucosa were analyzed. Furthermore, histological analysis and electron microscopy analysis were applied to detect the histology changes of nasal mucosa and the infiltration of mast cells in nasal mucosa. The results showed that administration of CCR3shRNA could effectively inhibit the expression of the CCR3 gene in bone marrow, peripheral blood and nasal mucosa, which reduced the nasal symptoms, the level of OVA-specific IgE, the inflammatory cells and mast cells infiltration into nasal cavity, and relieved the histopathological changes of nasal mucosa. In addition, intervention of CCR3shRNA could reduce the levels of the histamine, tryptase and PGD2 in bone marrow, peripheral blood and nasal mucosa. These results suggest that inhibition of CCR3 gene expression by shRNAs lentiviral vectors can effectively attenuate migration, infiltration and degranulation of mast cells in local tissues and alleviate the inflammation of allergic rhinitis mice.

Azelastine potentiates antiasthmatic dexamethasone effect on a murine asthma model.

Glucocorticoids are among the most effective drugs to treat asthma. However, the severe adverse effects associated generate the need for its therapeutic optimization. Conversely, though histamine is undoubtedly related to asthma development, there is a lack of efficacy of antihistamines in controlling its symptoms, which prevents their clinical application. We have reported that antihistamines potentiate glucocorticoids’ responses in vitro and recent observations have indicated that the coadministration of an antihistamine and a synthetic glucocorticoid has synergistic effects on a murine model of allergic rhinitis. Here, the aim of this work is to establish if this therapeutic combination could be beneficial in a murine model of asthma. We used an allergen‐induced model of asthma (employing ovalbumin) to evaluate the effects of the synthetic glucocorticoid dexamethasone combined with the antihistamine azelastine. Our results indicate that the cotreatment with azelastine and a suboptimal dose of dexamethasone can improve allergic lung inflammation as shown by a decrease in eosinophils in bronchoalveolar lavage, fewer peribronchial and perivascular infiltrates, and mucin‐producing cells. In addition, serum levels of allergen‐specific IgE and IgG1 were also reduced, as well as the expression of lung inflammatory‐related genes IL‐4, IL‐5, Muc5AC, and Arginase I. The potentiation of dexamethasone effects by azelastine could allow to reduce the effective glucocorticoid dose needed to achieve a therapeutic effect. These findings provide first new insights into the potential benefits of glucocorticoids and antihistamines combination for the treatment of asthma and grants further research to evaluate this approach in other related inflammatory conditions.

RmIL-33-stimulated nuocytes promote allergic inflammation in mouse model of allergic rhinitis

Objective:The study aimed to investigate the role of nuocytes in allergic rhinitis （AR） murine models. Method:After intranasal administration of recombinant （rm） interleukin （IL）-33 in BALB/c mice, nuocytes were sorted and purified from the mouse nasal-associated lymphoid tissue （NALT）. Then, we examined the response of nuocytes to rmIL-33 in vitro. After a murine model of AR was established using ovalbumin, we adoptively transferred the cultured NALT-derived nuocytes to mice models, and determined allergic responses in them. Result:rmIL-33 expanded nuocytes in NALT of mice compared with AR mice （t=3.66, P<0.01）, and increased production of IL-13 from these cells in vitro in comparison with unstimulated nuocytes （t=19.90, P<0.000 1）. After adoptive transfer of nuocytes, sneezing （t=9.89, P<0.000 1） ,numbers of eosinophils（t=8.17, P<0.000 1）, concentrations of IL-13 （t=40.47, P<0.000 1） and IL-33 （t=19.89, P<0.000 1） in nasal lavage fluid were all enhanced when compared with AR mice. Conclusion:Nuocytes promote allergic inflammation in a murine model of AR.

Letter to the Editor Regarding “Sublingual Immunotherapy Attenuates Nasal Symptoms upon Allergen Exposure in Murine Allergic Rhinitis Model via an Induction of IL-10 producing T cells in Submandibular Lymph Node”

Letter to the Editor Regarding “Sublingual Immunotherapy Attenuates Nasal Symptoms upon Allergen Exposure in Murine Allergic Rhinitis Model via an Induction of IL-10 producing T cells in Submandibular Lymph Node”

Mal-deficiency impairs the tolerogenicity of dendritic cell of patients with allergic rhinitis

The tolerogenic dendritic cell dysfunction is associated with the pathogenesis of immune diseases. Microbial stimulus is required in the maintenance of immune functions. This study aims to elucidate the role of Mal signal in the maintenance of DEC205+ DC (decDC) immune tolerogenic function. In this study, peripheral DCs were collected from allergic rhinitis (AR) patients and healthy control (HC) subjects to assess the functional status of decDCs. An AR murine model was developed to test the role of Mal signals in the maintenance of decDCs’ functions. We observed that AR decDCs (decDCs obtained from AR patients) were incompetent in the induction of type 1 regulatory T cells (Tr1 cells). AR decDCs expressed less IL-10 than that in HC decDCs. IL-10 mRNA decayed spontaneously in AR decDCs. Tat-activating regulatory DNA-binding protein-43 (TDP43) protected IL-10 mRNA from decay. AR decDCs expressed lower levels of Mal than that in HC decDCs. Mal depletion resulted in IL-10 mRNA decay in HC decDCs. Reconstitution of Mal in AR decDCs restored the capacity of inducing Tr1 cells and attenuated experimental AR in mice. In conclusion, Mal plays a critical role in the maintenance of decDC’s immune tolerogenic function. The absence or insufficient Mal signal impairs decDC’s tolerogenic property. Reconstitution of Mal in AR decDCs can restore the immune tolerogenic capacity, which may have translational potential in the treatment of AR and other allergic diseases.

Sublingual Immunotherapy Attenuates Nasal Symptoms Upon Allergen Exposure in Murine Allergic Rhinitis Model via an Induction of IL-10 producing T cells in Submandibular Lymph Node.

Sublingual immunotherapy has been considered to be a painless and effective therapeutic treatment of patients with allergic rhinitis. Its mechanism of action has been elucidated, but there are still controversies among many reports between clinical efficacy and laboratory data. Therefore, its mechanism of action needs to be investigated further by using promising animal models such as rodents and monkeys. Bearing this in mind, in our present study, we successfully constructed an effective murine model for sublingual immunotherapy (SLIT) in allergic rhinitis in which mice were sublingually administered ovalbumin (OVA), followed by intraperitoneal (ip) sensitization and intranasal (i.n.) challenge of OVA. To summarize our experimental data, nasal symptoms such as sneezing and nasal rubbing of sublingually treated mice were significantly attenuated in accordance with lower specific IgE antibodies in sera. Histological analysis of eosinophil recruitment in nasal mucosae reveals less allergic inflammation in sublingually treated mice. Interleukin-10 (IL-10) production and IL-10-specific mRNA gene expression of cultured submandibular lymph node (SMLN) cells with OVA, obtained from sublingually treated mice, were significantly higher than those of mice without sublingual treatment. These results demonstrate that sublingually introduced antigens can actually attenuate nasal symptoms in a murine allergic rhinitis model upon allergen exposures. Furthermore, our immunological data might indicate an important role of IL-10 producing T cells in SMLN to control nasal allergic reaction.

Intervention of Orai1 Influences the Response of Nuocytes From Allergic Rhinitis Mice to IL-33.

Nuocytes are essential in innate type-2 immunity and contribute to the exacerbation of allergic rhinitis (AR). This study aimed to evaluate the intervention of Orai1 on the response of nuocytes from AR mice to interleukin (IL)-33. We established a murine model of AR. Nuocytes were obtained from the mouse nasal-associated lymphoid tissue. Then, we assessed expressions of Orai1, Ca2+ mean fluorescence intensity (MFI) in nuocytes, and their cellular response to mouse recombinant (rm) IL-33. After that, we administered rmlentivirus vectors (lenti) that encoded small hairpin RNA (shRNA) against ORAI1 (lenti-ORAI1) into nuocytes cultures and again evaluated Orai1 and Ca2+ MFI in nuocytes and their response to rmIL-33. Finally, we adoptively transferred nuocytes alone or nuocytes transfected by lenti or lenti-ORAI1 to AR models to investigate their roles during allergic inflammation. We showed that Orai1 and Ca2+ MFI were upregulated in AR mice nuocytes. These cells were induced to produce more IL-5 and IL-13 by rmIL-33. However, the intervention of Orai1 by lenti-ORAI1 in nuocytes decreased Orai1 and Ca2+ MFI and reduced productions of aforementioned cytokines even after the administration of rmIL-33. Numbers of sneezing, nasal rubbing, and counts of eosinophils were all enhanced after the adoptive transfer of nuocytes. Concentrations of IL-5, IL-13, and IL-33 in the nasal lavage fluid (NLF) of allergic mice were also increased. However, the adoptive transfer of nuocytes transfected by lenti-ORAI1 decreased aforementioned parameters. These findings show that the intervention of Orai1 in nuocytes influences the response of nuocytes to rmIL-33.

Nonylphenol can aggravate allergic rhinitis in a murine model by regulating important Th cell subtypes and their associated cytokines

Nonylphenol (NP) is a widely distributed, toxic endocrine-disrupting chemical exhibiting estrogenic activity. However, its effect on allergic rhinitis (AR) remains unclear. In this study, the effects of NP on a murine model of AR were investigated. Mice were divided into ovalbumin (OVA), NP, and control groups. OVA was used for sensitization and challenge. Mice in the NP group were administered NP during the sensitization period. Allergic nasal symptoms and eosinophil counts in nasal mucosa were measured. Serum levels of OVA-specific IgE were determined by enzyme-linked immunosorbent assay. The mRNA levels of transcription factors of Th cells were determined with real-time polymerase chain reaction. Th cell subtypes and Treg numbers were counted with the aid of multi-color flow cytometry. Cytokine concentrations in nasal mucosa were determined using the cytometric bead array method. Subcutaneous injection of NP into mice exhibiting AR enhanced not only the nasal allergic symptoms, but also eosinophil infiltration and OVA-specific IgE. Moreover, NP upregulated IL-4, IL-5, IL-13, IL-9, IL-6 and IL-17, and downregulated IL-10, in the AR mouse model; IFN-γ and IL-23 were not affected. Transcription factors and Th cell percentages were evaluated to determine whether NP regulates Th cell subtypes in an AR mouse model. GATA3, PU.1, and RORγt levels were significantly increased, but FoxP3 and Helios were decreased. In addition, Th2, Th9, and Th17 subtype percentages significantly increased, and Treg cell percentages decreased, in NP administration groups; the percentage of Th1 subtypes was not affected. NP enhanced allergic inflammation in the AR mouse model through upregulation of Th2, Th9, and Th17 responses and negative regulation of Treg responses. These results suggest that NP may be trigger AR.

Therapeutic effect of topical administration of red onion extract in a murine model of allergic rhinitis

The aim of this study was to evaluate the effect of topical administration of onion (Allium cepa) extract on nasal cavity for treatment of allergic rhinitis (AR). BALB/c mice were sensitized by intraperitoneal injection of ovalbumin (OVA) and challenged with intranasal instillation of OVA with or without onion extracts for five times a week on 3 consecutive weeks. Allergic symptom score according to frequencies of sneezing, serum total and OVA specific immunoglobulin E (IgE) level, cytokine levels of nasal mucosa and eosinophilic infiltration were analyzed. Allergic symptom score, serum total and OVA specific IgE, cytokine levels of nasal mucosa (interleukin (IL)-4, IL-5, IL-10, IL-13, IFN-γ, TNF-α and COX-2) and eosinophilic infiltration were higher in allergic mouse group than negative control group. Topical application of onion extracts significantly reduced allergic symptoms and OVA specific IgE levels. Cytokine levels of IL-4, IL-5, IL-10, IL-13 and IFN-γ were significantly decreased in groups treated with onion extract. In addition, eosinophil infiltration of nasal turbinate mucosa was also significantly decreased after treatment with onion extract. Topical administration of onion extract significantly reduces allergic rhinitis symptom and allergic inflammatory reaction in a murine allergic model. It can be assumed that the topical application of onion extract regulates allergic symptoms by suppressing the type-1 helper (Th1) and type-2 helper (Th2) responses and reducing the allergic inflammatory reaction.

Sublingual administration of liposomes enclosing alpha-galactosylceramide as an effective adjuvant of allergen immunotherapy in a murine model of allergic rhinitis

BackgroundSublingual immunotherapy (SLIT) is an established efficacious approach for the treatment of allergic rhinitis (AR). However, SLIT requires a long administration period to establish stable and adequate responses. This study investigated the efficacy of the sublingual administration of an allergen with liposomes enclosing α-GalCer (α-GC-liposome) as a potential adjuvant in mice with AR. MethodsMice with AR induced by OVA received the sublingual administration of OVA, α-GC-liposomes, or OVA plus α-GC-liposomes for 7 days. After nasal re-challenge with OVA, nasal symptoms were evaluated. The serum levels of OVA-specific Ig, the cytokine production of CD4+ T cells in the cultures of cervical lymph node (CLN) cells, and the gene expression of CLNs were analyzed. ResultsAlthough IL-4, IL-5 and IL-13 production from CD4+ T cells in CLN cells was significantly inhibited by the sublingual administration of OVA alone in mice with AR induced by OVA, their nasal symptoms were not significantly diminished. However, the combined sublingual administration of α-GC-liposomes and OVA completely suppressed nasal symptoms, downregulated Th2 and Th17 type cytokine production in CD4+ T cells as well as Th2 and Th17 gene expressions, and upregulated Th1 type cytokine production as well as Th1 gene expressions in CLN cells. Additionally, the serum levels of specific IgG2a were promoted, and specific IgE and IgG1 were inhibited. ConclusionsOur findings suggest that the sublingual administration of an allergen with α-GC-liposomes as an adjuvant might increase the therapeutic efficacy and effectiveness of this treatment method.

Changes among TGF-β1+ Breg cells and helper T cell subsets in a murine model of allergic rhinitis with prolonged OVA challenge

BackgroundAllergic rhinitis is a common allergic disease resulting from inappropriate Th2 cell-mediated immune responses to environmental antigens. As such, regulatory B cells and T helper cells play a critical role in the occurrence and development of allergic rhinitis. MethodsWild-type mice received ovalbumin (OVA) intranasal challenge for varied lengths of time, then the inflammatory state of their nasal mucosa was analyzed by histology. Changes to the proportion and function of TGF-β1+ Bregs, T helper cells and plasma cells was analyzed by flow cytometry, real-time PCR, ELISA and cytometric bead arrays. Finally, changes in expression of upstream transcription factors related to helper T cells and STAT proteins were detected by western blot. ResultsThe most severe inflammatory response was observed in the mucosal tissue, where the percentage of TGF-β1+ Bregs and Tregs decreased, and the percentage and function of Th2 and plasma cells increased significantly. With prolonged OVA challenge, the proportion of TGF-β1+ Bregs and Tregs increased. These factors regulated Th2 cell polarization state and gradually restored balance of the inflammatory state in the nasal mucosa. Moreover, changes to upstream transcription factors and STAT proteins were found to be positively correlated with changes to helper T cells. ConclusionTGF-β1+ Bregs cooperated with Treg cells in the development of allergic rhinitis and its recovery process. Reconstitution of nasal mucosal immunity was facilitated via regulation of the proportion and function of helper T cells.

IL-37 attenuates allergic process via STAT6/STAT3 pathways in murine allergic rhinitis

Allergic rhinitis (AR) is a common upper airway allergic disease caused by allergens triggering a type 2 immune response. The imbalance of CD4+ T cell subsets is the essential immunological feature of AR, which is mainly characterized by the predominance of T helper (Th) 2 cells. Recent studies indicated that the anti-inflammatory factor interleukin (IL)-37 is involved in the immune regulation of AR. However, the mechanism of IL-37 acts on AR has not been fully elucidated. Thus, we sought to assess the protective role of IL-37 in AR and further explore the possible mechanism. An ovalbumin (OVA)-induced AR murine model was established. After IL-37 treatment, the allergic symptoms (sneezes and nasal rubbings), nasal mucosal infiltration with eosinophils, and serum IgE production were found significantly attenuated. For CD4+ T cell subsets, the proliferation and differentiation of Th2 and Th17 cells were restrained. The relevant effector cytokines of IL-4, IL-5, IL-6, and IL-17a protein expression and transcription factors GATA3 and RORγt mRNA levels were obviously decreased. However, IL-37 had no significant effect on Th1 and Treg response including in IFN-γ, IL-10, T-bet, and Foxp3 expression. Furthermore, IL-37 was found down-regulated the STAT6, STAT3, phospho-STAT6, and phospho-STAT3 expression. In conclusion, IL-37 alleviates allergic inflammation in AR possibly through repressing STAT6 and STAT3 signaling pathways.

CD4+ T cells induce productions of IL-5 and IL-13 through MHCII on ILC2s in a murine model of allergic rhinitis

ObjectiveCD4+ T cells play an important role not only in the induction of allergy but also in allergic inflammation. Group 2 innate lymphoid cells (ILC2s) also mediate type 2 immune responses in allergic rhinitis (AR). However, the relationships between CD4+ T cells and ILC2s in allergic condition are currently not well defined. The study aimed to evaluate the potential influences of CD4+ T cells on ILC2s in the murine model of AR. MethodsA murine model of AR was established using ovalbumin (OVA), and OVA-induced ILC2s were sorted and purified from the mouse nasal-associated lymphoid tissue (NALT), and cultured in vitro. Then, the expression of major histocompatibility complex class II (MHCII) on ILC2s was examined. CD4+ T cells were separated from AR mice peripheral blood mononuclear cells (PBMCs). After that, productions of IL-5 and IL-13 on ILC2s cultures were assessed when CD4+ T cells or plus anti-MHCII antibody or anti-CD4 antibody were administered into the cultures. Finally, we adoptively transferred ILC2s alone or ILC2s plus anti-MHCII antibody to the murine model of AR to investigate their roles in the nasal allergic inflammation. ResultsWe showed that ILC2s could be induced by OVA in the mouse NALT. The number and percentage of ILC2s in AR mice were increased. MHCII was expressed on ILC2s, and its protein and mRNA were all enhanced in allergic condition. IL-5 and IL-13 proteins and mRNAs were elevated after CD4+ T cells administration, and were reduced after these cells plus anti-MHCII antibody or anti-CD4 antibody application. Numbers of sneezing and nasal rubbing as well as counts of eosinophils in nasal lavage fluid (NLF) were all enhanced after the adoptive transfer of ILC2s when compared to AR mice. IL-5 and IL-13 in the NLF of allergic mice were also increased in comparison with AR group. However, above parameters were all decreased after the transfer of ILC2s plus anti-MHCII antibody versus AR mice or ILC2s-treated ones. ConclusionThese findings show that CD4+ T cells induce productions of IL-5 and IL-13 through MHCII on ILC2s in AR mice models.

Ethanol extract of Dryopteris crassirhizoma alleviates allergic inflammation via inhibition of Th2 response and mast cell activation in a murine model of allergic rhinitis

Ethnopharmacological relevanceDryopteris crassirhizoma (DC) is used as a traditional herbal remedy to treat various diseases, the tapeworm infection, common cold, and cancer in Korea, Japan, and China. DC also has the antioxidant anti-inflammatory and antibacterial activities. However, the anti-allergic inflammatory effect of DC and some of its mechanisms in allergic rhinitis model are unknown well. Aim of this studyThe purpose of this study is to investigate the anti-allergic inflammatory effect of DC on the allergic rhinitis model, mast cell activation and histamine release. Materials and methodsAllergic rhinitis was induced in BALB/c mice by sensitization and challenge with ovalbumin (OVA). Different concentration of DC and dexamethasone was administrated by oral gavage on 1 h before the OVA challenge. Mice of the control group were treated with saline only. Then mice were evaluated for the presence of nasal mucosa inflammation, the production of allergen-specific cytokine response and the histology of nasal mucosa. ResultsDC significantly ameliorated the nasal symptoms and the inflammation of nasal mucosa. DC also reduced the infiltration of eosinophils and mast cells in these tissues and the release of histamine in blood. Meanwhile, DC evidently inhibited the overproduction of Th2 cytokines and increased the Th1 and Treg cytokines in nasal lavage fluid by OVA. DC also reduced the levels of OVA-specific IgE, IgG1 and IgG2a in blood. ConclusionsThis study suggests that DC has a significant anti-allergic inflammatory effect in the nasal cavity. DC may have the therapeutic effect of allergic rhinitis.

OK-432 Administration Inhibits Murine Allergic Rhinitis at the Induction Phase, through the Macrophage Activation with TLR2 Signaling Pathway.

OK-432, a preparation of a low-virulence strain (Su) of Streptococcus pyogenes (Group A) killed by a penicillin and lyophilized, is a stiff inducer of Th1 cytokines, and exerts anti-cancer effects in tumor-bearing mice. OK-432 has been reported to consist of many bacterial components, such as peptidoglycan, M-protein, etc. However, it is yet to be ascertained which bacterial component induces T helper 1 (Th1) responses. For the last decade, Toll-like receptor (TLR) family proteins are well elucidated to play a role in recognizing bacterial components and inducing interleukin (IL)-12 from macrophages. Above all, peptidoglycan seems to be the agonist of TLR2 rather than the obverse. In our present study, the role of TLR2 for the recognition of OK-432 by macrophages and the effects of OK-432 are examined on murine allergic rhinitis model. Interestingly, results show IL-12 production by macrophages derived from TLR2 knock-out (ko) mice was significantly decreased, in comparison with that of macrophages derived from wild-type mice. Moreover, in TLR2 ko mice, no regulatory effect of OK-432 was observed on an allergic rhinitis model. These data indicate that TLR2 signaling is involved in regulating OK-432-induced anti-T helper 2 (Th2) immunity, and may offer a new prophylactic and therapeutic approach using OK-432 to downregulate allergic disorders, such as allergic rhinitis.

PM2.5 exposure exacerbates allergic rhinitis in mice by increasing DNA methylation in the IFN-γ gene promoter in CD4+T cells via the ERK-DNMT pathway

Allergic rhinitis (AR) is a common chronic inflammatory disease that has a significant impact on the quality of life of patients. Our previous study suggested that PM2.5 might affect pediatric AR through epigenetic regulation, but the underlying mechanisms remained unclear. In this study, an experimental murine AR model was created, and the nasal symptoms, pathological changes, the DNA methylation level of the IFN-γ gene promoter and activation of the ERK-DNMT pathway were evaluated after treatment with PM2.5. Our results showed that PM2.5 exposure led to more severe symptoms of AR in mice. In addition, PM2.5 exposure significantly decreased the percentage of Th1 T cells in the AR group, and this change was correlated with increased DNA methylation of the IFN-γ gene promoter in CD4 + T cells (r=-0.916, p = 0.029). In addition, PM2.5 exposure increased the activation of the ERK-DNMT pathway in CD4+ T cells, and inhibiting this effect rescued the polarization of the Th1/Th2 balance toward Th2, thereby decreasing the risk of AR. Our findings demonstrate that PM2.5 exposure could exacerbate AR by increasing the DNA methylation of the IFN-γ gene promoter in CD4 + T cells via the ERK-DNMT pathway, and these effects were rescued when the ERK-DNMT pathway was inhibited.

Beneficial effects of hydrogen gas inhalation on a murine model of allergic rhinitis.

Allergic rhinitis (AR) is a common chronic inflammatory condition. It has been previously indicated that oxidative stress may contribute to allergic inflammation, including AR. Although molecular hydrogen (H2), an antioxidative agent, has been effective in treatment of numerous oxidative stress-associated diseases, the effect of inhalation of a high concentration of H2 on AR remains unknown. In the current study, female BALB/c mice were sensitized with ovalbumin (OVA) followed by intranasal OVA challenge to establish an animal model of AR. Mice were subjected to exposure to H2 and the inert gas helium at different frequencies and durations. The frequencies of sneezing/scratching and the body weights of mice were recorded. Histological analysis and multiplex cytokine assays were performed to evaluate the effects of H2 on AR. Challenge with OVA induced significant nasal mucosa inflammation. H2 inhalation reduced the infiltration of inflammatory cells into mucosa and lowered the levels of interleukin (IL)-5, IL-13 and monocyte chemoattractant protein-1 in serum. H2 inhalation slightly increased the level of interferon-γ, however the difference was not statistically significant. Treatment with H2 limited the weight increase in healthy mice and reversed the weight loss in mice with AR. Furthermore, H2 inhalation induced a therapeutic effect on AR in a dose-dependent manner. The current results demonstrate that H2 may demonstrate a therapeutic value for allergic diseases.

Immunomodulatory effect of Bifidobacterium breve on experimental allergic rhinitis in BALB/c mice.

Bifidobacterium breve (B. breve) may have a beneficial effect on allergic rhinitis (AR). The aim of the present study was to investigate whether microbial induction of regulatory T cells (Tregs) and adjustment of Th1 and Th2 responses by B. breve are associated with protection against allergic inflammation, and to identify a dose-response association in a murine AR model. Ovalbumin (OVA)-sensitized BALB/c mice were orally treated with different doses of B. breve [1010, 109, 107 and 105 colony forming units (CFU)]. Following nasal challenge with OVA, sneeze frequency, serum OVA-specific immunoglobulin E (IgE) and cytokine concentrations [interleukin (IL)-4, IL-10, IL-13 and interferon-γ], splenic percentage of cluster of differentiation (CD)4+CD25+ Tregs, and morphology of the nasal mucosa were examined. Oral treatment with live B. breve at doses of 107 CFU or higher alleviated nasal mucosal injury and suppressed sneezing upon repeated administration over a 6-week period. Furthermore, treatment with B. breve at these higher doses reduced the concentrations of serum OVA-specific IgE, IL-4 and IL-10, and increased the splenic percentage of CD4+CD25+ Tregs in rhinitic mice compared with those who did not receive probiotics. In contrast, treatment with B. breve at a lower dose did not indicate any effect on sneezing frequency or mucosal morphology in this animal model, even though the splenic percentage of CD4+CD25+ Tregs increased and the concentrations of serum OVA-specific IgE and IL-10 declined. B. breve exerts its anti-allergic effects by inhibiting type 2 helper T cell immune responses and enhancing CD4+CD25+ Treg activity. Sneezing was also reduced at a dose of 107 CFU or higher. The current study investigated the role of B. breve and aided in identifying the optimal dose of B. breve administration in the treatment of AR.