ResearchArticle IL-18 Does not Increase Allergic Airway Disease in Mice When Produced by BCG
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The increase in the incidence of allergic disorders especially in developed countries may be explained by the hygiene hypothesis. A novel therapeutic approach that causes a Th1-dominant response under conditions of Th2-skewed immunity has been investigated. Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is a widely used anti-tuberculosis vaccine that strongly induces a Th1-predominant immune response. A potential role for BCG in the treatment of allergic diseases has been reported. In the present study, we investigated whether subcutaneous inoculation with a low dose (1 × 105) of BCG vaccine can attenuate allergic inflammation of the airway in a murine model of asthma. Female BALB/c mice were vaccinated on day 0 with a subcutaneous. injection of 1 × 105 CFU of BCG, and sensitized to ovalbumin (OVA, i.p., with alum) on day 7 and 14, respectively. After a 2-week interval, they were exposed to aerosolized OVA (1%). In another experiment, BCG-sensitized splenic CD4+ T cells were adoptively transferred before sensitization. We found that BCG-vaccinated mice had fewer eosinophils in BALF and less severe allergic inflammation. The expression of IL-4 as well as Eotaxin and TARC was down-regulated in the vaccinated mice, while that of both IL-12 and IFN-γ was up-regulated. Moreover, the transfer of splenic CD4+ T cells from vaccinated mice into naive mice before OVA-sensitization prevented the development of allergic inflammation. These splenic CD4+ T cells produced much IFN-γ. The subcutaneous administration of (low-dose) BCG vaccine suppressed allergic inflammation via Th1-skewed immunity and might have clinical applications in immunotherapy for asthma.
Subcutaneous injection
Allergic Inflammation
Adoptive Cell Transfer
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<b><i>Background:</i></b> Interleukin 27 (IL-27) is an initiator of the Th1 response and inhibits inflammatory responses. In a mouse model of asthma, administration of IL-27 reduced eosinophil numbers in bronchoalveolar lavage fluid and airway hyperresponsiveness. However, it is unclear whether administration of IL-27 can inhibit symptoms of allergic diseases and allergic rhinitis as a therapeutic agent. Therefore, we investigated the in vivo effect of IL-27 on nasal symptoms and allergic rhinitis. <b><i>Methods:</i></b> Mice sensitized and challenged with ovalbumin (OVA) antigen received intranasal administration of IL-27. <b><i>Results:</i></b> Intranasal administration of IL-27 significantly suppressed the number of sneezes and nasal rubbing movements, the number of eosinophils, OVA-specific T-cell responses in cervical lymph nodes, production of IL-4 and IL-5, and OVA-specific IgE in sera, compared with the administration of PBS alone. The production of IL-10 and IL-35, the percentage of CD25+Foxp3+ cells, and the gene expression of Foxp3 in mice that received intranasal administration of IL-27 were also significantly higher than those in mice that received only PBS. <b><i>Conclusions:</i></b> This study showed, for the first time, that intranasal administration of IL-27 inhibited nasal allergic responses and symptoms even after the establishment of allergic rhinitis and suggested that IL-27 is useful as an intranasal therapeutic agent.
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Bronchial hyperresponsiveness
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We have developed in C57 Black 6 mice an in vivo model of allergic airway inflammation characterized by the presence of IgE antibodies to an inhaled antigen, peribronchial infiltrates with an increased number of eosinophils, and an increased airway responsiveness to nonantigenic bronchoconstrictor stimuli. In this animal model we have investigated the role of different cytokines in the development of IgE antibodies to inhaled antigen, eosinophilic airway inflammation, and airway hyperresponsiveness. The studies were performed by using knockout mice or by exogenous administration of cytokines or cytokine antagonists. Interleukin-4 (IL-4) knockout mice were unable to develop an allergic eosinophilic airway infiltration and did not produce specific IgE antibodies. Chronic aerosol exposure to antigen also did not induce an increase in airway responsiveness. In studies of wild-type mice, pretreatment with the combination of anti-IL5 and anti-IL-5 receptor antibodies, given in an attempt to fully inhibit the effect of endogenously released IL-5, caused a pronounced inhibition of the antigen-induced airway eosinophilia but did not prevent the increase in airway responsiveness. Treatment with IL-12 during the active immunization prevented airway eosinophilia, production of specific IgE antibodies, and the antigen-induced increase in airway responsiveness. In contrast, administration of IL-12 to actively immunized mice during the aerosol exposure abolished airway eosinophilia and airway hyperresponsiveness without affecting the production of specific IgE.
Pulmonary Eosinophilia
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Antibody titer
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Allergic asthma is thought to be regulated by Th2 cells, and inhibiting this response is a promising mode of intervention. Many studies have focused on differentiation of Th cells to the Th1 or Th2 subset in vitro. IL-4 is essential for Th2 development, while IL-12 induces Th1 development, which can be enhanced by IL-18. In the present study, we investigated whether IL-12 and IL-18 were able to interfere in Th2 development and the associated airway symptoms in a mouse model of allergic asthma. Mice were sensitized with OVA using a protocol that induces IgE production. Repeated challenges by OVA inhalation induced elevated serum levels of IgE, airway hyperresponsiveness, and a predominantly eosinophilic infiltrate in the bronchoalveolar lavage concomitant with the appearance of Ag-specific Th2-like cells in lung tissue and lung-draining lymph nodes. Whereas treatments with neither IL-12 nor IL-18 during the challenge period were effective, combined treatment of IL-12 and IL-18 inhibited Ag-specific Th2-like cell development. This inhibition was associated with an absence of IgE up-regulation, airway hyperresponsiveness, and cellular infiltration in the lavage. These data show that, in vivo, the synergistic action of IL-12 and IL-18 is necessary to prevent Th2-like cell differentiation, and consequently inhibits the development of airway symptoms in a mouse model of allergic asthma.
Pulmonary Eosinophilia
Interleukin 13
Bronchial hyperresponsiveness
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We analyzed the effects of different administration routes and application times of the BCG-Moreau strain on airway and lung inflammation and remodeling in a murine model of allergic asthma. BALB/c mice (n = 168) were divided into two groups. The first group received BCG-Moreau strain while the second group received saline using the same protocol. BCG or saline were intradermally or intranasally injected one or two months before the induction of asthma. Mice were further sensitized and challenged with ovalbumin or received saline. Twenty-four hours after the last challenge, BCG prevented the triggering of pro-inflammatory cytokines, probably by increasing Foxp3 and interleukin (IL)-10, modulating eosinophil infiltration and collagen fiber deposition, thus reducing airway hyperresponsiveness. In conclusion, BCG-Moreau prevented lung remodeling in the present model of allergic asthma, regardless of administration route and time of vaccination. These beneficial effects may be related to the increase in regulatory T cells and to IL-10 production in tandem with decreased Th2 cytokines (IL-4, IL-5, and IL-13).
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BALB/c
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Allergic Inflammation
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Airway hyperresponsiveness
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