Mucosal tolerance as therapy of type I allergy: intranasal application of recombinant Bet v 1, the major birch pollen allergen, leads to the suppression of allergic immune responses and airway inflammation in sensitized mice

Winkler, Birgit; Baier, K.; Wagner, Stefan; Repa, Andreas; Eichler, Hans‐Georg; Scheiner, Otto; Kraft, Dietrich; Wiedermann, Ursula

doi:10.1046/j.0022-0477.2001.01214.x

Cited by 48 publications

(51 citation statements)

References 41 publications

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“…As examples, intranasal application of recombinant birch allergen Bet v1 led to the suppression of the allergic immune response in sensitized mice (56), and continuous intranasal exposure to OVA in sensitized BALB/c animals led to the complete abrogation of airway inflammation (53). However, the effectiveness of mucosal OVA administration in suppressing T-cell immunity declined when mucosal antigen delivery started after immunization and became selective for the Th2-mediated pulmonary allergic response but not for T-cell-mediated antibody production (29).…”

Section: Discussionmentioning

confidence: 99%

Intranasal Coadministration of Live Lactococci Producing Interleukin-12 and a Major Cow's Milk Allergen Inhibits Allergic Reaction in Mice

Cortes-Perez

Ah‐Leung

Bermúdez‐Humarán

et al. 2007

Clin Vaccine Immunol

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The Th1/Th2 balance deregulation toward a Th2 immune response plays a central role in allergy. We previously demonstrated that administration of recombinant Lactococcus lactis strains expressing bovine ␤-lactoglobulin (BLG), a major cow's milk allergen, partially prevents mice from sensitization. In the present study, we aimed to improve this preventive effect by coadministration of L. lactis BLG and a second recombinant L. lactis strain producing biologically active interleukin-12 (IL-12). This L. lactis strain producing IL-12 was previously used to enhance the Food allergies, i.e., immediate-type, immunoglobulin E (IgE)-mediated immune responses, affect 2 to 2.5% of the general populations of Western countries (22,24,25). It results from the activation of the Th2-type helper lymphocytes. In mice, this response is mainly characterized by the production of interleukin-4 (IL-4) and IL-13, which induce the production of IgE and IgG1, and of IL-5, which attracts eosinophils. In contrast, the Th1 response is characterized by the induction of gamma interferon (IFN-␥) and IL-2 production and the stimulation of cellular immunity. Th1 and Th2 cells regulate their own development via the cytokines produced: IFN-␥ suppresses Th2-cell proliferation and promotes Th1-cell proliferation, whereas IL-4 promotes additional Th2-cell proliferation and inhibits Th1-cell development (39,43,45).A recent study suggests that an early allergen-specific induction of Th1 cells before allergy sensitization could not efficiently prevent the development of atopic disorders: Th1 priming was abolished in the presence of allergen-specific Th2 cells, whereas Th1 cells could not inhibit subsequent priming of Th2 cells (58). The use of adjuvants that increase the proliferation of Th1 cells and that render them more efficient in inhibiting Th2 cells would therefore be of great interest in the management of allergic diseases. These observations prompted us to explore the adjuvant effect of IL-12 in a mouse model of allergic reaction to bovine ␤-lactoglobulin (BLG), a major milk allergen (2). IL-12 is a heterodimeric cytokine produced by antigen-presenting cells that promotes the development of naïve Th cells into Th1 effector cells and that induces IFN-␥ production (51,52,54). IL-12 also inhibits Th2 class switching by repression of the IL-4 cytokine (15,17,46,54,55). Moreover, treatment with recombinant IL-12 has been shown to have positive effects on bronchial hyperresponsiveness and the eosinophilic response (11). Unfortunately, despite the therapeutic potential of this molecule, the toxicity of systemic IL-12 treatment observed during clinical trials has limited its use (18,31,32,33,40). This toxicity correlates with increased IFN-␥ levels, decreased glucose levels, and altered histological responses in the spleen and duodenum. This has motivated several recent investigations demonstrating that intranasal delivery of IL-12 is a less toxic route of inoculation compared to the commonly used systemic one (6,7,26).The gram-positive and nonpathogenic...

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Section: Discussionmentioning

confidence: 99%

Intranasal Coadministration of Live Lactococci Producing Interleukin-12 and a Major Cow's Milk Allergen Inhibits Allergic Reaction in Mice

Cortes-Perez

Ah‐Leung

Bermúdez‐Humarán

et al. 2007

Clin Vaccine Immunol

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“…Therefore, the local increment of IgA in response to LNIT may contribute to its improved effectiveness in protecting Th2-sensitized mice from airway allergen challenge. With respect to the use of recombinant allergens for mucosal tolerance induction as a treatment strategy against allergic sensitization, it has been shown in a murine model of birch pollen allergy that intranasal application of recombinant Bet v 1 (the major birch pollen allergen) led to significant responses in naive and in sensitized mice [27]; more importantly, the immunosuppression effect of LNIT with rBet v 1 was able to be directed against rBet v 1 itself, as well as towards the whole pollen [28]. In our study, similar results were found for LNIT with rDer p 2 in conjunction with FIP which did not only downregulate rDer p 2-sensitized mice but also those mice sensitized by Der p.…”

Section: Discussionmentioning

confidence: 99%

Production of Salivary Immunoglobulin A and Suppression of <i>Dermatophagoides pteronyssinus</i>-Induced Airway Inflammation by Local Nasal Immunotherapy

Liu¹,

Tsai²

2005

Int Arch Allergy Immunol

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Background: Local nasal immunotherapy (LNIT) is an effective immunotherapeutic modality, especially when targeting a single immunodominant peptide from an allergen. However, the working mechanisms of LNIT are poorly understood. We hypothesized that LNIT with a mixture of group 2 allergens of Dermatophagoides pteronyssinus (Der p 2) protein and fungal immunomodulatory peptide (FIP) would generate suppression of Der p-induced airway inflammation through immunoglobulin (Ig) A secretion in the airways. Method: Mice were sensitized with recombinant Der p 2 (rDer p 2) and Der p followed by LNIT with rDer p 2 in conjunction with FIP. After intratracheal challenge with rDer p 2 and Der p, the airway inflammation was determined by analyzing the cell subpopulation and cytokine concentration in the bronchoalveolar lavage fluid. The allergen-specific IgE, IgG2a and IgG in the sera and IgA in the saliva were measured by ELISA. Results: LNIT with rDer p 2 in conjunction with FIP could downregulate the lymphocyte infiltration in both rDer p 2- and Der p-induced airway inflammation. Both total and specific IgA in the saliva were increased after LNIT. Serum levels of IL-4, IL-10 and specific IgE were reduced and the specific IgG2a and IgG increased after LNIT. After LNIT, there was a reduction of airway hypersensitivity at 30 min after allergen challenge in the rDer p 2-and Der p-sensitized mice, with a significant decrease only in rDer p 2-sensitized mice. Conclusion: LNIT with rDer p 2 in conjunction with FIP was not only able to suppress rDer p 2-induced airway inflammation but also generate suppression of Der p-induced airway inflammation. The simultaneous reduction of IL-4 and IL-10 indicated that IL-10-producing cells were not activated by LNIT. The increment of IgA in the airway might play a role in the prevention of airway inflammation.

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“…IFN-g was measured by ELISA as previously described [23]. All other cytokines were measured with commercially available mouse ELISA kits; IL-4 and IL-5 (Endogen, Woburn, MA, USA), IL-13 and eotaxin (R & D Systems, MN, USA), with sensitivities of < 5 pg/ml for IL-4 and IL-5, < 1·5 pg/ml for IL-13 and < 3 pg/ml for eotaxin.…”

Section: Cytokine Analysismentioning

confidence: 99%

Influence of the route of sensitization on local and systemic immune responses in a murine model of type I allergy

Repa

Wild²,

Hufnagl³

et al. 2004

Clinical and Experimental Immunology

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SUMMARYThe pathophysiological and immunological characteristics of allergic immune responses are controlled by a variety of factors. We have studied the extent to which the route of sensitization influences allergenspecific IgE synthesis and local airway inflammation using a mouse model of allergic sensitization to the major birch pollen allergen Bet v 1. Sensitization of BALB/c mice with recombinant (r)Bet v 1 was performed using intraperitoneal (IP), subcutaneous (SC) or aerosol (AS) sensitization protocols. Mice were analysed for allergen-specific serum antibodies by ELISA and IgE-dependent basophil degranulation. Proliferative responses and cytokine production of splenocytes were measured upon Bet v 1 stimulation in vitro . Bronchoalveolar lavages were performed after airway challenge with aerosolized birch pollen extract for assessment of eosinophilic airway inflammation and local cytokine production in vivo. Highest allergen specific IgE levels and IgE-dependent basophil degranulation were achieved using the SC route. High IL-5 production by spleen and lung cells was associated with pronounced eosinophilia in bronchoalveolar lavages. After IP sensitization, despite giving the highest IgG levels, only low IgE levels, basophil degranulation and IL-5 production were seen. On the other hand, AS sensitization, resulting in the lowest systemic IgE and IL-5 levels, led to a comparably strong airway inflammation as the SC route. Our finding that the route of sensitization can result in a dissociation of local and systemic immune responses may contribute to a better understanding of the pathogenesis of allergic diseases and help to develop new treatment strategies.Keywords type I allergy murine model sensitization route local immune response systemic immune response

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Mucosal tolerance as therapy of type I allergy: intranasal application of recombinant Bet v 1, the major birch pollen allergen, leads to the suppression of allergic immune responses and airway inflammation in sensitized mice

Cited by 48 publications

References 41 publications

Intranasal Coadministration of Live Lactococci Producing Interleukin-12 and a Major Cow's Milk Allergen Inhibits Allergic Reaction in Mice

Intranasal Coadministration of Live Lactococci Producing Interleukin-12 and a Major Cow's Milk Allergen Inhibits Allergic Reaction in Mice

Production of Salivary Immunoglobulin A and Suppression of <i>Dermatophagoides pteronyssinus</i>-Induced Airway Inflammation by Local Nasal Immunotherapy

Influence of the route of sensitization on local and systemic immune responses in a murine model of type I allergy

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