Fcγ receptor‐mediated antigen uptake by lung DC contributes to allergic airway hyper‐responsiveness and inflammation

During asthma, lung DC capture and process antigens to initiate and maintain allergic Th2 cell responses to inhaled allergens. The aim of the study was to investigate whether allergen‐specific IgG, generated during sensitization, can potentiate the acute airway inflammation through Fcγ receptor (FcγR)‐mediated antigen uptake and enhance antigen presentation resulting in augmented T‐cell proliferation. We examined the impact of antigen presentation and T‐cell stimulation on allergic airway hyperresponsiveness and inflammation using transgenic and gene‐deficient mice. Both airway inflammation and eosinophilia in bronchoalveolar lavage fluid were markedly reduced in sensitized and challenged FcγR‐deficient mice. Lung DC of WT, but not FcγR‐deficient mice, induced increased antigen‐specific CD4⁺ T‐cell proliferation when pulsed with anti‐OVA IgG immune complexes. Intranasal application of anti‐OVA IgG immune complexes resulted in enhanced airway inflammation, eosinophilia and Th2 cytokine release, mediated through enhanced antigen‐specific T‐cell proliferation in vivo. Finally, antigen‐specific IgG in the serum of sensitized mice led to a significant increase of antigen‐specific CD4⁺ T‐cell proliferation induced by WT, but not FcγR‐deficient, lung DC. We conclude that FcγR‐mediated enhanced antigen presentation and T‐cell stimulation by lung DC has a significant impact on inflammatory responses following allergen challenge in asthma.     

Basophils as a primary inducer of the T helper type 2 immunity in ovalbumin‐induced allergic airway inflammation

Antigen‐induced allergic airway inflammation is mediated by T helper type 2 (Th2) cells and their cytokines, but the mechanism that initiates the Th2 immunity is not fully understood. Recent studies show that basophils play important roles in initiating Th2 immunity in some inflammatory models. Here we explored the role of basophils in ovalbumin (OVA) ‐induced airway allergic inflammation in BALB/c mice. We found that OVA sensitization and challenge resulted in a significant increase in the amount of basophils in blood and lung, along with the up‐regulation of activation marker of CD200R. However, depletion of basophils with MAR‐1 or Ba103 antibody attenuated airway inflammation, represented by the significantly decreased amount of the Th2 subset in spleen and draining lymph nodes, interlukin‐4 level in lung and OVA‐special immunoglobulin E (sIgE) levels in serum. On the other hand, adoptive transfer of basophils from OVA‐challenged lung tissue to naive BALB/c mice provoked the Th2 immune response. In addition, pulmonary basophils from OVA‐challenged mice were able to uptake DQ‐OVA and express MHC class II molecules and CD40 in vivo, as well as to release interleukin‐4 following stimulation by IgE–antigen complexes and promote Th2 polarization in vitro. These findings demonstrate that basophils may participate in Th2 immune responses in antigen‐induced allergic airway inflammation and that they do so through facilitating antigen presentation and providing interleukin‐4.     

Staphylococcus aureus enterotoxin B facilitates allergic sensitization in experimental asthma

Background Staphylococcus aureus Enterotoxin B (SEB) has immunomodulatory effects in allergic airway disease. The potential contribution of SEB to the sensitization process to allergens remains obscure. Objective In order to study the effects of staphylococcal‐derived toxins on the sensitization to ovalbumin (OVA) and induction of allergic airway inflammation, we have combined the nasal application of OVA with different toxins. Methods Nasal applications of OVA and saline, SEA, SEB, toxic shock syndrome toxin (TSST)‐1, protein A or lipopolysaccharide (LPS) were performed on alternate days from day 0 till 12. On day 14, mice were killed for the evaluation of OVA‐specific IgE, cytokine production by mediastinal lymph node (MLN) cells and bronchial hyperreactivity (BHR) to inhaled metacholine. The effect of SEB on dendritic cell (DC) migration and maturation, and on T cell proliferation was evaluated. Results Concomitant endonasal application of OVA and SEB resulted in OVA‐specific IgE production, whereas this was not found with SEA, TSST‐1, protein A, LPS or OVA alone. Increased DC maturation and migration to the draining lymph nodes were observed in OVA/SEB mice, as well as an increased T cell proliferation. Bronchial inflammation with an influx of eosinophils and lymphocytes was demonstrated in OVA/SEB mice, together with hyperresponsiveness and the production of IL‐4, IL‐5, IL‐10 and IL‐13 by MLN stimulated with OVA. Conclusions Our data demonstrate that SEB facilitates sensitization to OVA and consecutive bronchial inflammation with features of allergic asthma. This is likely due to augmentation of DC migration and maturation, as well as the allergen‐specific T cell proliferation upon concomitant OVA and SEB application. Cite this as: W. Huvenne, I. Callebaut, M. Plantinga, J. A. J. Vanoirbeek, O. Krysko, D. M. A. Bullens, P.Gevaert, P. Van Cauwenberge, B. N. Lambrecht, J. L. Ceuppens, C. Bachert and P. W. Hellings, Clinical & Experimental Allergy, 2010 (40) 1079–1080.     

T cells are necessary for ILC2 activation in house dust mite‐induced allergic airway inflammation in mice

Allergic asthma is a chronic inflammation of the airways mediated by an adaptive type 2 immune response. Upon allergen exposure, group 2 innate lymphoid cells (ILC2s) can be rapidly activated and represent an early innate source of IL‐5 and IL‐13. Here, we used a house dust mite (HDM)‐driven asthma mouse model to study the induction of ILC2s in allergic airway inflammation. In BALF, lungs, and lymph nodes, ILC2 activation is critically dependent on prior sensitization with HDM. Importantly, T cells are required for ILC2 induction, whereby T‐cell activation precedes ILC2 induction. During HDM‐driven allergic airway inflammation the accumulation of ILC2s in BALF is IL‐33 independent, although infiltrating ILC2s produce less cytokines in Il33^?/? mice. Transfer of in vitro polarized OVA‐specific OT‐II Th2 cells alone or in combination with Th17 cells followed by OVA and HDM challenge is not sufficient to induce ILC2, despite significant eosinophilic inflammation and T‐cell activation. In this asthma model, ILC2s are therefore not an early source of Th2 cytokines, but rather contribute to type 2 inflammation in which Th2 cells play a key role. Taken together, ILC2 induction in HDM‐mediated allergic airway inflammation in mice critically depends on activation of T cells.     

Targeting SIRP‐α protects from type 2‐driven allergic airway inflammation

The interplay between innate and adaptive immune responses is essential for the establishment of allergic diseases. CD47 and its receptor, signal regulatory protein α (SIRP‐α), govern innate cell trafficking. We previously reported that administration of CD47^+/+ but not CD47^−/− SIRP‐α⁺ BM‐derived DC (BMDC) induced airway inflammation and Th2 responses in otherwise resistant CD47‐deficient mice. We show here that early administration of a CD47‐Fc fusion molecule suppressed the accumulation of SIRP‐α⁺ DC in mediastinal LN, the development of systemic and local Th2 responses as well as airway inflammation in sensitized and challenged BALB/c mice. Mechanistic studies highlighted that SIRP‐α ligation by CD47‐Fc on BMDC did not impair Ag uptake, Ag presentation and Ag‐specific DO11.10 Tg Th2 priming and effector function in vitro, whereas in vivo administration of CD47‐Fc or CD47‐Fc‐pretreated BMDC inhibited Tg T‐cell proliferation, pinpointing that altered DC trafficking accounts for defective Th priming. We conclude that the CD47/SIRP‐α axis may be harnessed in vivo to suppress airway SIRP‐α⁺ DC homing to mediastinal LN, Th2 responses and allergic airway inflammation.     

A prostacyclin agonist with thromboxane inhibitory activity for airway allergic inflammation in mice

Background ONO‐1301 is a novel drug that acts as a prostacyclin agonist with thromboxane A₂ (TxA₂) synthase inhibitory activity. We investigated the effect of ONO‐1301 on development of airway allergic inflammation. Methods Mice sensitized and challenged to ovalbumin (OVA) received ONO‐1301, OKY‐046 (TxA₂ synthase inhibitor), beraprost, a prostacyclin receptor (IP) agonist, ONO‐1301 plus CAY10449 (selective IP antagonist) or vehicle during the challenge period. Twenty‐four hours after the OVA challenge, airway hyperresponsiveness (AHR) to methacholine was assessed and bronchoalveolar lavage was performed. Lung specimens were excised for goblet cell staining and analysis of lung dendritic cells (DCs). Bone marrow‐derived dendritic cells (BMDCs) were generated, in the presence or absence of drugs, for analysis of DC function. Results Mice that received ONO‐1301 showed significantly lower AHR, airway eosinophilia, T‐helper type 2 cytokine levels, mucus production and lung DCs numbers than vehicle‐treated mice. These effects of ONO‐1301 were mostly reversed by CAY10449. BMDCs treated with ONO‐1301 alone showed lower DC functions, such as expression of costimulatory factors or stimulation to spleen T cells. Conclusions These data suggest that ONO‐1301 may suppress AHR and airway allergic inflammation through modulation of DCs, mainly mediated through the IP receptor. This agent may be effective as an anti‐inflammatory drug in the treatment of asthma. Cite this as: M. Hayashi, T. Koya, H. Kawakami, T. Sakagami, T. Hasegawa, H. Kagamu, T. Takada, Y. Sakai, E. Suzuki, E. W. Gelfand and F. Gejyo, Clinical & Experimental Allergy, 2010 (40) 317– 326.     

Selective depletion of Foxp3+ Treg during sensitization phase aggravates experimental allergic airway inflammation

Recent studies highlight the role of Treg in preventing unnecessary responses to allergens and maintaining functional immune tolerance in the lung. We investigated the role of Treg during the sensitization phase in a murine model of experimental allergic airway inflammation by selectively depleting the Treg population in vivo. DEpletion of REGulatory T cells (DEREG) mice were depleted of Treg by diphtheria toxin injection. Allergic airway inflammation was induced using OVA as a model allergen. Pathology was assessed by scoring for differential cellular infiltration in bronchoalveolar lavage, IgE and IgG1 levels in serum, cytokine secretion analysis of lymphocytes from lung draining lymph nodes and lung histology. Use of DEREG mice allowed us for the first time to track and specifically deplete both CD25⁺ and CD25^? Foxp3⁺ Treg, and to analyze their significance in limiting pathology in allergic airway inflammation. We observed that depletion of Treg during the priming phase of an active immune response led to a dramatic exacerbation of allergic airway inflammation in mice, suggesting an essential role played by Treg in regulating immune responses against allergens as early as the sensitization phase via maintenance of functional tolerance.     

Prior SO2 exposure promotes airway inflammation and subepithelial fibrosis following repeated ovalbumin challenge

Background Exposure to allergens or air pollutants often leads to asthma exacerbations associated with aggravation of airway inflammation. Although, repeated allergen challenge often induces chronic allergic airway inflammation (CAAI) and airway remodelling, yet, the effects of brief exposure to air pollutants such as SO₂ on development of CAAI and airway remodelling remain to be clarified. Objective The aim of the experiment was to investigate the effects of acute neutrophilic airway inflammation induced by brief exposure to SO₂ on development of CAAI and subepithelial fibrosis (SEF) in a murine model of asthma. Methods Acute airway inflammation was induced by brief exposure to 50 p.p.m. SO₂ (1 h/d, 3 days). CAAI and SEF in BALB/c mice were induced by repeated challenge with ovalbumin (OVA) for 5 or 9 weeks with or without prior exposure to SO₂. Bronchoalveolar lavage fluid (BALF) eosinophilia as index of CAAI, BALF endothelin‐1 (ET‐1) and TGF‐β1 levels, morphometric evaluation of fibrotic area beneath subbasement membrane and lung hydroxyproline content (Hyp) as indexes of SEF were monitored. Results Exposure to SO₂ led to acute neutrophilic inflammation and epithelial sloughing with profound elevation of BALF ET‐1. Repeated OVA challenge resulted in CAAI and SEF along with elevation of Hyp, increase of fibrotic area beneath subbasement membrane and elevation of BALF TGF‐β1. Preceding SO₂ exposure exaggerated BALF eosinophilia, facilitated and enhanced SEF with more significant elevation of BALF ET‐1 and TGF‐β1 levels compared with OVA‐challenged mice without prior exposure to SO₂. The increase of Hyp was positively correlated with elevation of BALF TGF‐β1 during CAAI (r=0.842, P<0.01). Conclusion This data demonstrated that SEF developed in parallel with severity and time course of CAAI following repeated OVA challenge. SO₂‐induced acute epithelial injury and neutrophilic inflammation could enhance CAAI and promote SEF, probably through overexpression of ET‐1 and TGF‐β1.     

Infection with the roundworm Toxocara canis leads to exacerbation of experimental allergic airway inflammation

Background Epidemiological studies performed in developing as well as in western countries suggest that infection with Toxocara canis contributes to the development of atopic diseases. Objectives To investigate the association between infection with this helminth and allergy, we examined the effect of T. canis infection on experimental allergic airway inflammation. Methods BALB/c mice were infected by oral administration with 500 embryonated T. canis eggs followed by ovalbumin (OVA) sensitization and challenge to induce allergic airway inflammation. Results Infection with T. canis in combination with OVA treatment leads to exacerbation of pulmonary inflammation, eosinophilia, airway hyperresponsiveness, OVA specific and total IgE. Relative quantification of cytokine expression in the lungs of these mice showed increased expression of IL‐4 compared with mice that were only T. canis infected or OVA treated. Increased expression of IL‐5 and IL‐10 was measured in the lungs of T. canis‐infected or OVA‐treated mice compared with controls; however, combining infection and OVA treatment did not significantly change the expression of these cytokines. Conclusion A previous infection with T. canis leads to exacerbation of experimental allergic airway inflammation. These results have important consequences for findings on the helminths–allergy association. Several factors, including parasite species, infection of definitive vs. accidental host, parasite load and timing of infection, may influence whether an infection with helminths protects one from or enhances allergic manifestations.     

CD4+CD25+ T cell depletion impairs tolerance induction in a murine model of asthma

Background Regulatory T cells (Tregs) are key players in controlling the development of airway inflammation. However, their role in the mechanisms leading to tolerance in established allergic asthma is unclear. Objective To examine the role of Tregs in tolerance induction in a murine model of asthma. Methods Ovalbumin (OVA) sensitized asthmatic mice were depleted or not of CD25⁺ T cells by anti‐CD25 PC61 monoclonal antibody (mAb) before intranasal treatment (INT) with OVA, then challenged with OVA aerosol. To further evaluate the respective regulatory activity of CD4⁺CD25⁺ and CD4⁺CD25^? T cells, both T cell subsets were transferred from tolerized or non‐tolerized animals to asthmatic recipients. Bronchoalveolar lavage fluid (BALF), T cell proliferation and cytokine secretion were examined. Results Intranasal treatment with OVA led to increased levels of IL‐10, TGF‐β and IL‐17 in lung homogenates, inhibition of eosinophil recruitment into the BALF and antigen specific T cell hyporesponsiveness. CD4⁺CD25⁺Foxp3⁺ T cells were markedly upregulated in lungs and suppressed in vitro and in vivo OVA‐specific T cell responses. Depletion of CD25⁺ cells before OVA INT severely hampered tolerance induction as indicated by a strong recruitment of eosinophils into BALF and a vigorous T cell response to OVA upon challenge. However, the transfer of CD4⁺CD25^? T cells not only suppressed antigen specific T cell responsiveness but also significantly reduced eosinophil recruitment as opposed to CD4⁺CD25⁺ T cells. As compared with control mice, a significantly higher proportion of CD4⁺CD25^? T cells from OVA treated mice expressed mTGF‐β. Conclusion Both CD4⁺CD25⁺ and CD4⁺CD25^? T cells appear to be essential to tolerance induction. The relationship between both subsets and the mechanisms of their regulatory activity will have to be further analyzed.     

Attenuated Bordetella pertussis vaccine strain BPZE1 modulates allergen‐induced immunity and prevents allergic pulmonary pathology in a murine model

Background Virulent Bordetella pertussis, the causative agent of whooping cough, exacerbates allergic airway inflammation in a murine model of ovalbumin (OVA) sensitization. A live genetically attenuated B. pertussis mucosal vaccine, BPZE1, has been developed that evokes full protection against virulent challenge in mice but the effect of this attenuated strain on the development of allergic responses is unknown. Objective To assess the influence of attenuated B. pertussis BPZE1 on OVA priming in a murine model of allergic airway inflammation. Methods Mice were challenged with virulent or attenuated strains of B. pertussis, and sensitized to allergen (OVA) at the peak of bacterial carriage. Subsequently, airway pathology, local inflammation and OVA‐specific immunity were examined. Results In contrast to virulent B. pertussis, live BPZE1 did not exacerbate but reduced the airway pathology associated with allergen sensitization. BPZE1 immunization before allergen sensitization did not have an adjuvant effect on allergen specific IgE but resulted in a statistically significant decrease in airway inflammation in tissue and bronchoalveolar lavage fluid. BPZE1 significantly reduced the levels of OVA‐driven IL‐4, IL‐5 and IL‐13 but induced a significant increase in IFN‐γ in response to OVA re‐stimulation. Conclusions These data demonstrate that, unlike virulent strains, the candidate attenuated B. pertussis vaccine BPZE1 does not exacerbate allergen‐driven airway pathology. BPZE1 may represent an attractive T‐helper type 1 promoting vaccine candidate for eradication of whooping cough that is unlikely to promote atopic disease.     

Anti-asthma potential of crocin and its effect on MAPK signaling pathway in a murine model of allergic airway disease

Abstract

Context: Crocin, a diterpenoid glucoside, has multitudinous activities such as anti-inflammation, anti-allergy, anti-oxidation and relaxing smooth muscles.

Objective: In this study, the potential of crocin as an anti-asthma agent was investigated in a murine model.

Materials and methods: BALB/c mice were sensitized and challenged by ovalbumin (OVA) to induce allergic airway inflammation, with crocin administered one hour before every OVA challenge. Airway hyper-reactivity was evaluated by lung function analysis systems. Leukocyte counts in bronchoalveolar lavage fluid (BALF) were measured by a hemocytometer and Diff-Quick-stained smears. Lung tissues were stained with hematoxylin–eosin, Congo red and methylene blue for histopathological inspection. Inflammatory mediators in serum, BALF and lung were measured by ELISA or RT-PCR. Effects of crocin on MAPK signaling pathways were investigated by western blot analysis.

Results: Crocin significantly suppressed airway inflammation and hyper-reactivity, reduced levels of BALF interleukin (IL-4), IL-5, IL-13 and tryptase, lung eosinophil peroxidase and serum OVA-specific IgE, and inhibited the expression of lung eotaxin, p-ERK, p-JNK and p-p38 in the OVA-challenged mice.

Conclusions: These results demonstrated that the suppression of crocin on airway inflammation and hyper-reactivity in a murine model, thus crocin might have a great potential to be a candidate for the treatment of asthma.     

EGF receptor activation during allergic sensitization affects IL‐6‐induced T‐cell influx to airways in a rat model of asthma

EGF receptor (EGFR) is involved in cell differentiation and proliferation in airways and may trigger cytokine production by T cells. We hypothesized that EGFR inhibition at the time of allergic sensitization may affect subsequent immune reactions. Brown Norway rats were sensitized with OVA, received the EGFR tyrosine kinase inhibitor, AG1478 from days 0 to 7 and OVA challenge on day 14. OVA‐specific IgE in serum and cytokines and chemokines in BAL were measured 24 h after challenge. To evaluate effects on airway hyperresponsiveness (AHR), rats were sensitized, treated with AG1478, intranasally challenged, and then AHR was assessed. Furthermore chemotactic activity of BALF for CD4⁺ T cells was examined. The eosinophils, neutrophils and lymphocytes in BAL were increased by OVA and only the lymphocytes were reduced by AG1478. OVA significantly enhanced IL‐6 concentration in BAL, which was inhibited by AG1478. However AHR, OVA‐specific IgE and IL‐4 mRNA expression in CD4⁺ T cells were not affected by AG1478. BALF from OVA‐sensitized/challenged rats induced CD4⁺ T‐cell migration, which was inhibited by both AG1478 treatment in vivo and neutralization of IL‐6 in vitro. EGFR activation during sensitization may affect the subsequent influx of CD4⁺ T cells to airways, mainly mediated through IL‐6.     

Heme oxygenase‐1 inhibits basophil maturation and activation but promotes its apoptosis in T helper type 2‐mediated allergic airway inflammation

The anti‐inflammatory role of heme oxygenase‐1 (HO‐1) has been studied extensively in many disease models including asthma. Many cell types are anti‐inflammatory targets of HO‐1, such as dendritic cells and regulatory T cells. In contrast to previous reports that HO‐1 had limited effects on basophils, which participate in T helper type 2 immune responses and antigen‐induced allergic airway inflammation, we demonstrated in this study, for the first time, that the up‐regulation of HO‐1 significantly suppressed the maturation of mouse basophils, decreased the expression of CD40, CD80, MHC‐II and activation marker CD200R on basophils, blocked DQ‐ovalbumin uptake and promoted basophil apoptosis both in vitro and in vivo, leading to the inhibition of T helper type 2 polarization. These effects of HO‐1 were mimicked by exogenous carbon monoxide, which is one of the catalytic products of HO‐1. Furthermore, adoptive transfer of HO‐1‐modified basophils reduced ovalbumin‐induced allergic airway inflammation. The above effects of HO‐1 can be reversed by the HO‐1 inhibitor Sn‐protoporphyrin IX. Moreover, conditional depletion of basophils accompanying hemin treatment further attenuated airway inflammation compared with the hemin group, indicating that the protective role of HO‐1 may involve multiple immune cells. Collectively, our findings demonstrated that HO‐1 exerted its anti‐inflammatory function through suppression of basophil maturation and activation, but promotion of basophil apoptosis, providing a possible novel therapeutic target in allergic asthma.     

Characteristic features of allergic airway inflammation in a murine model of infantile asthma

BACKGROUND: The pathophysiology of infantile asthma may differ from that in older children or in adults, partly because of the different immune response depending upon maturation. In adult mice, the sensitizing dose of antigen is known to be critical to the polarized development of helper T cell subsets and allergic airway inflammation. We wanted to know the characteristics of allergic airway inflammation of infantile asthma by developing a murine model. METHODS: BALB/C mice at different stages of maturation (juvenile: 3 days after birth; adult: 8 weeks of age) were sensitized with 10 or 1,000 microg ovalbumin (OVA) or vehicle. The animals were then challenged with aerosolized OVA or saline once a day during 6 consecutive days. After the final challenge, bronchial hyperresponsiveness (BHR), bronchoalveolar lavage fluid (BALF), histological changes in the airways and immunological status were examined. RESULTS: In both juvenile and adult animals, sensitization with 10 microg OVA induced the T helper 2 response (elevated IL-4 and decreased IFN-gamma levels). BHR, airway eosinophilia, the inflammatory cell infiltration, goblet cell metaplasia (GCM), and IgE antibody production were more prominent in animals given this dose than 1,000 microg OVA. Among these responses, GCM as well as BALF IL-4, and BHR were comparable between juvenile and adult animals, whereas other parameters were lower in juvenile animals, especially in those given 1,000 microg OVA. CONCLUSION: GCM and, consequently, airway mucus hypersecretion may be an important component of allergic airway inflammation in infantile asthma.     

Synthesized OVA323-339MAP octamers mitigate OVA-induced airway inflammation by regulating Foxp3 T regulatory cells

ABSTRACT: BACKGROUND: Antigen-specific immunotherapy (SIT) has been widely practiced in treating allergic diseases such as asthma. However, this therapy may induce a series of allergic adverse events during treatment. Peptide immunotherapy (PIT) was explored to overcome these disadvantages. We confirmed that multiple antigen peptides (MAPs) do not cause autoimmune responses, which led to the presumption that MAPs intervention could alleviate allergic airway inflammation without inducing adverse effects. RESULTS: In this study, synthesized OVA323-339MAP octamers were subcutaneously injected into ovalbumin (OVA)-sensitized and -challenged Balb/c mice to observe its effect on allergic airway inflammation, Th2 immune response, and immune regulating function. It was confirmed that OVA sensitization and challenge led to significant peritracheal inflammatory, cell infiltration, and intensive Th2 response. Treatment of OVA323-339MAP octomers in the airway inflammation mice model increased CD4+CD25+Foxp3+ T regulatory (Treg) cells and their regulatory function in peripheral blood, mediastinal draining lymph nodes, and the spleen. Furthermore, OVA323-339MAP increased IL-10 levels in bronchial alveolar lavage fluid (BALF); up-regulated the expression of IL-10,membrane-bound TGF-beta1, as well as Foxp3 in lung tissues; and up-regulated programmed death-1 (PD-1) and cytotoxic T lymphocyte associated antigen 4 (CTLA-4) on the surface of Treg cells. These results were further correlated with the decreased OVA specific immunoglobulin E (sIgE) level and the infiltration of inflammatory cells such as eosinophils and lymphocytes in BALF. However, OVA323-339 peptide monomers did not show any of the mentioned effects in the same animal model. CONCLUSIONS: Our study indicates that OVA323-339MAP had significant therapeutic effects on mice allergic airway inflammation by regulating the balance of Th1/Th2 response through Treg cells in vivo. Key words Allergic airway inflammation; Specific immunotherapy; Multiple antigen peptide.     

Aspergillus fumigatus regulates mite allergen‐pulsed dendritic cells in the development of asthma

Background The role in allergic asthma development of the immune response against fungi with concomitant exposure to other common aeroallergens has yet to be determined. In particular, there is little understanding of how inhaled fungi affect the host response to mite allergens. Objective To characterize the in vitro and in vivo effects of concurrent exposure of Aspergillus fumigatus (Af) and Dermatophagoides farinae (Derf) on dendritic cells (DCs) in the development of allergic asthma. Methods Murine bone marrow‐derived DCs were pulsed with Derf and/or live or heat‐inactivated Af. Cytokine production and the expression of pathogen recognition receptors (PRRs) were determined in vitro. Subsequently, these DCs were inoculated into the airway of naïve mice to assess the development of allergic airway inflammation in vivo. The effect of antibodies against PRRs was also evaluated. Results Live Af significantly enhanced IL‐10 production and the expression of Toll‐like receptor (TLR) 2 and Dectin‐1 in Derf‐pulsed DCs. Live Af infection significantly attenuated Derf‐pulsed DC‐induced allergic airway inflammation in vivo. Antibodies against either TLR2 or Dectin‐1 significantly reversed the inhibitory effects of live Af in the development of Derf‐pulsed DC‐induced allergic airway inflammation. Conclusion Concurrent exposure of DCs to fungal antigens has profound influences on the subsequent mite allergen‐induced allergic airway inflammation. Live Af could regulate the functions of airway DCs in the development of mite allergen‐induced allergic airway inflammation via regulation of their PRRs. Our results suggest that concurrent exposure to pathogens such as fungi and mite allergens has profound influences on the subsequent allergen‐induced allergic airway inflammation. Furthermore, modulating PRR signalling could provide a therapeutic regimen for the development of asthma. Cite this as: S. Fukahori, H. Matsuse, T. Tsuchida, T. Kawano, S. Tomari, C. Fukushima and S. Kohno, Clinical & Experimental Allergy, 2010 (40) 1507–1515.