COX-2 inhibition enhances the TH2 immune response to epicutaneous sensitization

BACKGROUND: Mechanical injury to the skin by scratching is an important feature of atopic dermatitis (AD). OBJECTIVE: To investigate the role of COX-2 in allergic skin inflammation elicited by epicutaneous (EC) sensitization via introduction of ovalbumin through shaved tape-stripped skin. METHODS: COX-2 mRNA was measured by quantitative PCR, and COX-2 protein was measured by Western blotting. We investigated the effect of administration of the COX-2 selective inhibitor NS-398 during EC sensitization with ovalbumin in a mouse model of AD characterized by eosinophil skin infiltration, elevated total and antigen specific IgE, and a systemic TH2 response to antigen. We further examined the response of COX-2-deficient mice to EC immunization with ovalbumin. RESULTS: Tape stripping caused a transient increase in skin COX-2 mRNA. In contrast, COX-2 mRNA was not increased after ovalbumin sensitization. Infiltration by eosinophils and expression of IL-4 mRNA in ovalbumin-sensitized skin sites, ovalbumin specific IgE and IgG1 antibody responses, and IL-4 secretion by splenocytes after ovalbumin stimulation were all significantly increased in EC mice that received NS-398. In contrast, ovalbumin specific IgG 2a antibody response and IFN-gamma secretion by splenocytes after ovalbumin stimulation were significantly decreased in these mice. COX-2-deficient mice also exhibited an enhanced systemic TH2 response to EC sensitization. CONCLUSION: These results demonstrate that COX-2 limits the TH2 response to EC sensitization and suggest that COX inhibitors may worsen allergic skin inflammation in patients with AD.     

Effects of TNCB sensitization in DS-Nh mice, serving as a model of atopic dermatitis, in comparison with NC/Nga mice

BACKGROUND: It has been predicted that a type-1 and type-2 helper T cell (Th1/Th2) imbalance exists in atopic dermatitis (AD). In DS-Nh mice, an AD mouse model, Staphylococcus aureus increases on the skin surface. OBJECTIVE: To investigate whether the Th1-dominant response has an influence on the development of AD, we induced chronic allergic hypersensitivity with 2,4,6-trinitrochlorobenzene (TNCB ) in two AD mouse models: NC/Nga mice and DS-Nh mice. Th1 and Th2 cytokine production of splenocytes was assessed under stimulation with staphylococcal enterotoxin B (SEB) which induces a Th1 response in DS-Nh mice with or without TNCB sensitization. METHODS: We examined clinical skin changes, transepidermal water loss (TEWL), the number of S. aureus on the skin and the serum IgE levels in these mice treated repeatedly with TNCB under conventional conditions (free of fur mites). The splenocytes of DS-Nh mice were cultured with SEB and the cytokine levels in the supernatants were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Significant skin changes were observed on the skin even where TNCB was not applied in both mice treated with TNCB. Increases in S. aureus on the skin and serum IgE levels were detected in DS-Nh mice, but not in NC/Nga mice. In DS-Nh mice, IFN-gamma and IL-13 production of splenocytes increased in the mice treated with TNCB. CONCLUSION: These results suggest that there might be a different mechanism of dermatitis induction between NC/Nga and DS-Nh mice. Th1 responses might play an important role in the development of dermatitis and increase in serum IgE levels in DS-Nh mice through an increase in IL-13 production.     

Influence of respiratory syncytial virus infection on cytokine and inflammatory responses in allergic mice

BACKGROUND: Th2 lymphocyte responses are associated with inflammation and disease during allergic responses. Exposure to particular environmental factors during the expression of allergy could result in more pronounced Th2-like immune responses and more severe disease. One factor might be a respiratory virus infection. OBJECTIVE: The aim of our study was to investigate the influence of respiratory syncytial virus (RSV) infection on the expression of ovalbumin (OVA)-induced allergy in BALB/c mice. METHODS: We determined OVA-specific IgE in serum, cytokine profiles and histopathological lesions in lungs of OVA-allergic mice after RSV infection. RESULTS: OVA sensitization and challenge induced OVA-specific IgE in serum, Th2 cytokine mRNA expression, and mononuclear and eosinophilic inflammation in the lungs. RSV inoculation during the challenge period enhanced OVA-induced IL-4 and IL-5 mRNA expression in lung tissue. RSV further enhanced the OVA-induced hypertrophy of mucous cells and eosinophilic infiltration in lung tissue. Surprisingly, RSV infection decreased Th2 cytokine secretion and eosinophilic influx in bronchoalveolar lavage of OVA-allergic mice. Because inactivated RSV did not influence these responses, replication of RSV appeared essential for the modification of OVA-induced Th2 cytokine expression. RSV did not change OVA-specific IgE levels in serum. Furthermore, the RSV-induced IL-12 mRNA expression in lung tissue of OVA-allergic mice was diminished, but IFN-gamma mRNA expression was not affected. CONCLUSION: RSV infection enhanced particular OVA-induced Th2 cytokine mRNA responses and pulmonary lesions in allergic mice and thus aggravated allergic respiratory disease.     

Respiratory syncytial virus, pneumonia virus of mice, and influenza A virus differently affect respiratory allergy in mice

BACKGROUND: Respiratory viral infections in early childhood may interact with the immune system and modify allergen sensitization and/or allergic manifestations. In mice, respiratory syncytial virus (RSV) infection during allergic provocation aggravates the allergic T helper (Th) 2 immune response, characterized by the production of IL-4, IL-5, and IL-13, and inflammatory infiltrates. However, it is unclear whether the RSV-enhanced respiratory allergic response is a result of non-specific virus-induced damage of the lung, or virus-specific immune responses. OBJECTIVE: In the present study we investigated whether RSV, pneumonia virus of mice (PVM) and influenza A virus similarly affect the allergic response. METHODS: BALB/c mice were sensitized and challenged with ovalbumin (OVA), and inoculated with virus during the challenge period. Pulmonary inflammation, lung cytokine mRNA responses, and IgE production in serum were assessed after the last OVA-challenge. RESULTS: Like RSV, PVM enhanced the OVA-induced pulmonary IL-4, IL-5, and IL-13 mRNA expression, which was associated with enhanced perivascular inflammation. In addition, PVM increased the influx of eosinophils in lung tissue. In contrast, influenza virus decreased the Th2 cytokine mRNA expression in the lungs. However, like PVM, influenza virus enhanced the pulmonary eosinophilic infiltration in OVA-allergic mice. CONCLUSION: The Paramyxoviruses RSV and PVM both are able to enhance the allergic Th2 cytokine response and perivascular inflammation in BALB/c mice, while the Orthomyxovirus influenza A is not.     

Mast cells regulate IFN-gamma expression in the skin and circulating IgE levels in allergen-induced skin inflammation.

BACKGROUND: Mast cells are important effector cells in IgE-mediated allergic reactions. They are present in normal skin and increased in skin lesions of patients with atopic dermatitis (AD). OBJECTIVE: We used mice deficient in mast cells (W/W(v)) to assess the role of these cells in a murine model of allergen-induced skin inflammation induced by repeated epicutaneous sensitization with ovalbumin (OVA); the model exhibits many of the characteristics of AD. METHODS: Mice deficient in mast cells were sensitized with OVA. Histologic and immunohistochemical examinations, as well as measurements of IL-4 and IFN-gamma mRNA, were performed on OVA-sensitized skin. Total and antigen-specific serum IgE levels were determined. RESULTS: Infiltration in W/W(v) mice by mononuclear cells, T cells, and eosinophils in OVA-sensitized skin was comparable to that in wild-type (WT) controls. Expression of IL-4 mRNA in sensitized skin sites was similarly increased in WT and W/W(v) mice. However, IFN-gamma mRNA expression was significantly increased in sensitized skin of W/W(v) mice but not in that of WT controls. IL-4 mRNA was readily detectable in unsensitized skin of WT controls but not in that of W/W,(v) mice, whereas expression of IL-12 p40 mRNA was significantly increased in unsensitized skin of W/W(v) mice in comparison with WT controls. Total serum IgE levels were significantly increased after epicutaneous sensitization in W/W(v) mice in comparison with WT controls. CONCLUSION: These results suggest that mast cells regulate IFN-gamma expression in the skin and IgE levels in the circulation in a model of allergen-induced skin inflammation with similarities to AD. This is important, given the role of IFN-gamma in keratinocyte injury in AD and the role of IgE-mediated reactions in exacerbating AD.     

Comparison of serum specific IgE antibodies to staphylococcal enterotoxins between atopic children with and without atopic dermatitis

BACKGROUND: The skin of patients with atopic dermatitis (AD) exhibits a striking susceptibility to colonization and infection by Staphylococcus aureus. The exotoxins secreted by S. aureus can act as superantigens and classic allergens, inducing the production of functionally relevant specific IgE antibodies. The aim of this study was to compare the levels and positive rates of serum staphylococcal enterotoxin A (SEA)- and staphylococcal enterotoxin B (SEB)-specific IgE between atopic children with and without AD. METHODS: Sixty children with AD, 55 children with respiratory allergy without AD, and 24 nonatopic healthy children were studied. The levels and positive rates of serum SEA- and SEB-specific IgE were compared among three groups. The correlation between the levels or positive rates of serum SEA/SEB-specific IgE and the severity of AD or the presence of previous skin infections was studied. RESULTS: The children with AD had significantly higher levels and positive rates of serum SEA- and SEB-specific IgE than the atopic children without AD (P < 0.001) and the nonatopic children (P < 0.001). There was no significant difference in the levels and positive rates of serum SEA- and SEB-specific IgE between the atopic children without AD and the nonatopic children. With or without adjustment for the potential confounding effect of total serum IgE levels, the levels and positive rates of serum SEA- and SEB-specific IgE were significantly correlated with severity of AD (P <0.005), but they were not significantly different between AD children with and without previous skin infections. CONCLUSIONS: SEA and SEB may contribute to chronic inflammation and exacerbation of AD through the IgE-mediated immune response.     

The complement component C3 plays a critical role in both Th1 and Th2 responses to antigen

BACKGROUND: Complement component C3 is synthesized by keratinocytes and is activated after skin injury. C3 is also synthesized by peritoneal macrophages, which are activated by the adjuvant alum. OBJECTIVE: We sought to investigate the role of C3 in inciting allergic skin Inflammation and systemic immune responses after epicutaneous sensitization or intraperitoneal sensitization with antigen. METHODS: C3-deficient (C3-/-) mice and wild-type (WT) control animals were subjected to epicutaneous sensitization with the antigen ovalbumin (OVA) on shaved and tape-stripped skin or intraperitoneal immunization with OVA in alum. RESULTS: Skin Infiltration by eosinophils and expression of mRNA encoding the TH2 cytokines IL-4 and IL-5 in OVA-sensitized skin sites was impaired in C3-/- mice. Splenocytes from epicutaneously sensitized C3-/- mice secreted less IL-4, IL-5, IL-13, and IFN-gamma in response to OVA stimulation than splenocytes from WT control animals. The defect in cytokine secretion by splenocytes was also observed after intraperitoneal immunization of C3-/- mice. C3-/- mice had impaired IgG1, IgG2a, and IgE antibody responses after both epicutaneous and intraperitoneal immunization. The defect in cytokine secretion of C3-/- mice was not due to defective proliferation to antigen, was not observed after anti-CD3 stimulation, and was corrected by the addition of purified C3 protein. CONCLUSION: These results suggest that C3 plays an important role in both the TH1 and TH2 response to antigen in vivo. CLINICAL IMPLICATIONS: The complement pathway might be a potential target in the therapy of allergic diseases.     

An obligate role for T-cell receptor alphabeta+ T cells but not T-cell receptor gammadelta+ T cells, B cells, or CD40/CD40L interactions in a mouse model of atopic dermatitis

BACKGROUND: We recently described a murine model of atopic dermatitis (AD) elicited by epicutaneous sensitization with ovalbumin (OVA). The skin lesions in these mice were characterized by a dermal infiltrate consisting of eosinophils and T cells and by increased expression of the TH2 cytokines IL-4 and IL-5. Epicutaneous sensitization induces a rise in the levels of serum total IgE and OVA-specific antibodies, further indicating that it elicits a predominantly TH2 response. OBJECTIVE: This study was undertaken to assess the roles of T cells, B cells, and CD40L-CD40 interactions in AD. METHODS: Mice with targeted gene deletions were sensitized with OVA. Histologic and immunohistochemical examinations, as well as measurements of IL-4 mRNA, were performed on OVA-sensitized skin. Total and antigen-specific serum IgE levels were determined. RESULTS: RAG2(-/-) mice, which lack both T and B cells, did not exhibit cellular infiltration, induction of dermal IL-4 mRNA, or elevation of serum IgE after OVA sensitization; all of these features were present in B-cell-deficient IgH(-/-) mice. T-cell receptor alpha(-/-) mice did not display cellular infiltration, IL-4 mRNA expression, or increased IgE levels after OVA sensitization, but these responses were elicited in T-cell receptor delta(-/-) mice after sensitization. Absence of CD40 had no effect on these responses. CONCLUSION: These results suggest that alphabeta T cells, but not gammadelta T cells, B cells, or CD40L-CD40 interactions, are critical for skin inflammation and the TH2 response in AD.     

Increased levels of serum-specific immunoglobulin e to staphylococcal enterotoxin a and B in patients with allergic rhinitis and bronchial asthma

BACKGROUND: The association between staphylococcal enterotoxins and atopic dermatitis (AD) is well characterized. We aim to evaluate the association between sensitization to staphylococcal enterotoxin A (SEA) and/or B (SEB) and the development of allergic airway disease. METHODS: Two hundred and seventy-four patients were grouped into allergic rhinitis (AR) and/or bronchial asthma (BA) only, AD only and AR/BA+AD. The AR/BA only group was further divided into AR only, AR and airway hyperresponsiveness (AR+AHR) and BA. The allergen-specific and total immunoglobulin E (IgE) antibodies were determined by the CAP system. The associations of sensitization to SEA/SEB with allergic airway disease were analyzed by logistic regression analysis. RESULTS: The overall rate of sensitization to SEA/SEB was 25.7%, whereas the rate of the AD only group (45.5%) was significantly higher than that of the AR/BA only group (24.5%, chi2=8.1). After sensitization to SEA/SEB, the geometric mean total IgE levels were significantly elevated in patients with AR+AHR and BA, but not in those with AR only. BA patients had higher geometric mean values of SEA- and SEB-specific IgE than AR only and AR+AHR patients. Logistic regression revealed that AR/BA only was more associated with sensitization to SEA/SEB (odds ratio 6.57) than AD only and AR/BA+AD (odds ratio 2.44 and 1.72). CONCLUSIONS: Atopic status after sensitization to SEA/SEB was more closely associated with BA than with other airway allergy, implying that SEA/SEB may play a role in exacerbating airway allergy and increasing the risk of allergic airway disease. Our study suggests that staphylococcal enterotoxins play a prominent role in the pathogenesis of allergic airway disease as well as AD.     

Suppression of allergic airway inflammation and IgE responses by a class I restricted allergen peptide vaccine

CD8 T cells are known to deviate CD4 T-cell responses from Th2 toward Th1. Reduction of Th2 cytokines and increased interferon-γ ameliorates allergic airway disease. We have developed a novel approach to the suppression of allergic airway inflammation, by designing a MHC class I-restricted allergen peptide vaccine, which induces potent and long-lived CD8 T-cell responses. Vaccination of C57BL/6 mice before allergen sensitization completely prevented allergen-specific immunoglobulin E (IgE) antibody responses. Vaccination after sensitization failed to suppress IgE, but inhibited accumulation of eosinophils and neutrophils in airways after subsequent allergen challenge. Vaccination suppressed Th2 airway infiltration and enhanced the lung Th1 response without inducing excessive CD8 cellular infiltration or interleukin-17, and the combination of class I peptide with adjuvant was more effective than adjuvant alone. Airway hyperreactivity was prevented by vaccination in an allergen-specific fashion. Class I peptide vaccines might therefore represent a robust and long-lasting immunotherapeutic strategy in allergic disease.     

Nasal exposure to Staphylococcal enterotoxin enhances the development of allergic rhinitis in mice

BACKGROUND: Staphylococcal enterotoxins (SEs) appear to play a role in the pathogenesis of allergic disease. However, little is known whether the nasal exposure to SE affects the development of allergic rhinitis (AR). OBJECTIVE: We sought to determine the in vivo effect of nasal exposure to SE on the development of AR using mouse model. METHODS: BALB/c mice were intranasally sensitized with Schistosoma mansoni egg antigen (SmEA) in the presence or absence of staphylococcal enterotoxin B (SEB). Control mice were intranasally sensitized with either SEB or SmEA alone. The production of antigen-specific antibodies including IgE, nasal eosinoplilia and cytokines by nasal mononuclear cells was compared among mice that had or had not received SEB treatment. RESULTS: Nasal exposure to SEB enhanced the development of AR in SmEA-sensitized mice, as manifested by SmEA-specific IgE production, nasal eosinophilia, and IL-4 and IL-5 production by nasal mononuclear cells after Ag challenge. This treatment also elicited IFN-gamma production by SmEA-primed cells. In addition, these mice produced SEB-specific IgE whereas mice treated with SEB without SmEA sensitization did not produce SEB-specific IgE or demonstrate nasal eosinophilia. CONCLUSION: These results suggest that the nasal exposure to SEB enhances susceptibility to AR although the exposure to SE solely does not induce AR.     

Protective effects of a recombinant fragment of human surfactant protein D in a murine model of pulmonary hypersensitivity induced by dust mite allergens

Lung surfactant protein D (SP-D) is a carbohydrate pattern recognition immune molecule. It can interact with a range of pathogens, stimulate immune cells and manipulate cytokine profiles during host's immune response. SP-D has also been shown to interact, via its carbohydrate recognition domains, with glycoprotein allergens of house dust mite (Dermatophagoides pteronyssinus, Derp), inhibiting specific IgE isolated from mite-sensitive asthmatic patients from binding these allergens, and blocking subsequent histamine release from sensitized basophils. In the present study, we have examined the protection offered by various doses of intranasal administration of a recombinant fragment of human SP-D (rhSP-D) in a murine model of pulmonary hypersensitivity to Derp allergens which showed characteristic high levels of specific IgE antibodies, peripheral blood eosinophilia, pulmonary infiltrates and a Th2 cytokine response. Treatment of Derp mice with rhSP-D led to significant reduction in Derp-specific IgE levels, blood eosinophilia and pulmonary cellular infiltration. The levels of IL-4 and IL-5 were decreased, while those of IL-12 and IFN-gamma were raised in the supernatant of the cultured splenocytes, indicating a Th2 to Th1 polarization. These results suggest that SP-D has a protective role in the modulation of allergic sensitization and in the development of allergic reactions to Derp allergens and highlight potential of the rhSP-D as a therapeutic for pulmonary hypersensitivity.     

Natural killer T cells are required for the development of a superantigen-driven T helper type 2 immune response in mice

We show, here, that one single injection or weekly injections of staphylococcal enterotoxin B (SEB), starting in 1-day-old newborn mice, induced a powerful immune response with a T helper type 2 (Th2) pattern, as judged by the isotype and cytokine profile, with the production of large amounts of SEB-specific immunoglobulin G1 (IgG1), detectable levels of SEB-specific IgE and increased production of interleukin-4 by spleen cells. These protocols also induced an increase in the levels of total IgE in the serum. Memory of SEB was transferred to secondary recipients by using total spleen cells from primed animals. The secondary humoral response in transferred mice was diminished if spleen cells from SEB-treated mice were previously depleted of CD3+ or Vbeta8+ T cells or NK1.1+ cells. In vivo depletion of NK1.1+ cells in adult mice resulted in a marked reduction in the SEB-specific antibody response in both the primary and secondary immune responses. Additionally, purified NK1.1+ T cells were able to perform SEB-specific helper B-cell actions in vitro and in vivo. These results suggest that NK1.1+ T cells are required for the full development of humoral immunological memory, whilst making neonatal tolerance to SEB unachievable.     

CD1d restricted natural killer T cells are not required for allergic skin inflammation

BACKGROUND: Invariant T-cell receptor-positive natural killer (iNKT) cells have been shown to be essential for the development of allergen-induced airway hyperreactivity (AHR). OBJECTIVE: We examined the role of iNKT cells in allergic skin inflammation using a murine model of atopic dermatitis (AD) elicited by epicutaneous sensitization with ovalbumin (OVA). METHODS: Wild-type (WT) and natural killer T-cell-deficient CD1d-/- mice were epicutaneously sensitized with OVA or normal saline and challenged with aerosolized OVA. iNKT cells in skin and bronchoalveolar lavage fluid were analyzed by fluorescence-activated cell sorting, and cytokine mRNA levels were measured by quantitative RT-PCR. AHR to methacholine was measured after OVA inhalation. RESULTS: Skin infiltration by eosinophils and CD4+ cells and expression of mRNA encoding IL-4 and IL-13 in OVA-sensitized skin were similar in WT and CD1d-/- mice. No significant increase in iNKT cells was detectable in epicutaneously sensitized skin. In contrast, iNKT cells were found in the bronchoalveolar lavage fluid from OVA-challenged epicutaneously sensitized WT mice, but not CD1d-/- mice. Epicutaneously sensitized CD1d-/- mice had an impaired expression of IL-4, IL-5, and IL-13 mRNA in the lung and failed to develop AHR in response to airway challenge with OVA. CONCLUSION: These results demonstrate that iNKT cells are not required for allergic skin inflammation in a murine model of AD, in contrast with airway inflammation, in which iNKT cells are essential. CLINICAL IMPLICATIONS: Understanding the potential role of iNKT cells in AD will allow us to have a more specific target for therapeutic use.     

Exposure to endotoxins during sensitization prevents further endotoxin-induced exacerbation of airway inflammation in a mouse model of allergic asthma

BACKGROUND: We have shown previously that lipopolysaccharides (LPS) inhibited airway inflammation in allergen-sensitized and challenged mice when administered during sensitization, while exacerbating the inflammation when given upon challenge. We have here investigated the effect of LPS administered during both sensitization and challenge on airway inflammation, as well as on the profile of the T-helper (Th) response to allergen. METHODS: Mice were sensitized and challenged with ovalbumin (OVA), in the presence or absence of effective doses of LPS, namely 1 mug during sensitization and 1 ng during challenge. Inflammation was assessed by measuring cell counts and cytokine levels in bronchoalveolar lavage fluid (BALF). The profile of the Th response was determined by quantifying OVA-specific IgE and IgG2a in serum and Th1/Th2 cytokines in the culture medium of splenocytes and in BALF. RESULTS: Allergen-induced airway eosinophilia was increased in mice exposed to LPS during challenge only when compared with controls, whereas it was similarly reduced in animals exposed during sensitization only and during both sensitization and challenge. Mice exposed to LPS during sensitization only or during both sensitization and challenge also displayed a decrease in IgE and an increase in IgG2a, suggesting a switch in the immune response toward the Th1 profile. This was confirmed by quantification of Th1/Th2 cytokines in culture medium of splenocytes and in BALF. CONCLUSIONS: Our data demonstrate that exposure to endotoxins during sensitization prevents allergen-induced airway inflammation, as well as its exacerbation triggered by further exposure to endotoxins during challenge, while switching the immune response to allergen from a Th2 to a Th1 profile.     

IL-15 prevents allergic rhinitis through reactivation of antigen-specific CD8+ cells

BACKGROUND: Allergic rhinitis is one of the most common allergic inflammatory diseases characterized by a predominant TH2 response with antigen-specific IgE synthesis. IL-15 plays important roles in activation and maintenance of memory CD8+T cells capable of producing IFN-gamma, which regulates TH2 responses. OBJECTIVE: To investigate the roles of endogenous IL-15 in allergic inflammation, we examined allergic rhinitis in IL-15 knockout (KO) mice sensitized with ovalbumin followed by intranasal rechallenge with ovalbumin. METHODS: IL-15KO mice were sensitized intraperitoneally with ovalbumin/complete Freund's adjuvant on day 0 and ovalbumin/IFA on day 7, and then were intranasally challenged with ovalbumin on days 21, 22, 23, 24, and 25. Nasal symptoms and histologic changes were examined. IgE production and TH2 responses were measured by ELISA. Purified CD8+T cells or recombinant IL-15 were administered into ovalbumin-sensitized mice. RESULTS: The levels of IgE production and TH2 responses in IL-15KO mice were comparable to those in control mice after ovalbumin sensitization. However, sneezing, infiltration of eosinophils into the nasal mucosa, and TH2 cytokine production were aggravated in ovalbumin-sensitized IL-15KO mice after intranasal challenge with ovalbumin. Adoptive transfer of CD8+6 T cells from ovalbumin-sensitized mice suppressed the TH2 responses in mice but not in IL-15KO mice. Administration of IL-15 with ovalbumin significantly prevented the development of allergic rhinitis in ovalbumin-sensitized mice. CONCLUSION: We demonstrate with IL-15KO mice that endogenous IL-15 plays an important role in suppression of allergic rhinitis at effector phase. Intranasal administration of IL-15 is useful as a therapeutic approach to control allergic rhinitis. CLINICAL IMPLICATIONS: Intranasal administration of recombinant IL-15 might become new immunotherapy for allergic rhinitis.     

Costimulatory molecule OX40L is critical for both Th1 and Th2 responses in allergic inflammation

T cell activation and cytokine secretion are important mediators of inflammation in allergic asthma. The costimulatory pathway CD28/CD80/CD86 has been shown to play an important role in T cell activation in allergic asthma, but less is known about the effect of other costimulatory molecules in allergy. The costimulatory molecule OX40 ligand (OX40L), a member of the tumor necrosis factor superfamily, has been shown to be important in T cell priming and cytokine production. We investigated the role of OX40L in a murine model of allergic inflammation using OX40L(-/-) mice. In this model, following OVA sensitization and challenge, mice develop features of allergic inflammation including elevated levels of total serum IgE, pulmonary eosinophils, cytokines, and pulmonary inflammation. In the absence of OX40L, total serum IgE, pulmonary eosinophils, cytokines, and pulmonary inflammation were all significantly reduced compared to wild-type controls. Levels of eotaxin mRNA, an eosinophil-specific chemoattractant, were also markedly reduced, paralleling the significant reduction in pulmonary eosinophils. Levels of allergen-induced Th1 as well as Th2 cytokines were also significantly reduced. Together, the data support a critical role for OX40L signals in allergic responses.     

Aggravation of bronchial eosinophilia in mice by nasal and bronchial exposure to Staphylococcus aureus enterotoxin B

BACKGROUND: The role of bacterial enterotoxins like Staphylococcus aureus enterotoxin B (SEB) in allergic asthma remains unknown. We used a mouse model of airway allergy to study the effects of nasal or bronchial contact with SEB on bronchial allergic inflammation. METHODS: The features of allergic asthma were induced in ovalbumin (OVA)-sensitized mice (days 1-13) by repeated exposures to nebulized OVA (days 33-37). Nasal or bronchial application of SEB was performed on three occasions (days 33-35-37), and the effects on bronchial inflammation, IgE titres and expression levels of mRNA for T helper type 2 cytokines and other inflammatory mediators were evaluated. RESULTS: Both nasal and bronchial SEB enhanced the allergen-induced bronchial inflammation, as reflected by more eosinophilic inflammation in the airway lumen and in bronchial tissue. Aggravation of experimental asthma correlated with higher expression of mRNA for IL-5, IL-4, IFN-gamma, IL-12 p40, eotaxin-1 and TGF-beta in bronchi. In addition, nasal SEB elevated concentrations of IL-4, IL-5 and IFN-gamma in serum and bronchial SEB increased titres of OVA-specific and total IgE in serum. CONCLUSION: Our data illustrate the potential of both nasal as well as bronchial SEB to aggravate several features of allergic asthma in a mouse model.