Intranasal tolerance induction with polypeptides derived from 3 noncross-reactive major aeroallergens prevents allergic polysensitization in mice

Hufnagl, Karin; Winkler, Birgit; Focke, M.; Valenta, Rudolf; Scheiner, Otto; Renz, Harald; Wiedermann, Ursula

doi:10.1016/j.jaci.2005.04.002

Cited by 37 publications

(43 citation statements)

References 38 publications

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“…In this study, we did not observe the production of cytokines such as IL-10 or TGF-␤ in BAL fluid or reactivated splenocytes in mice pretreated with BLG (data not shown). This suggests a cell-contact-dependent tolerance, which may involve CD4 ϩ T cells expressing membrane-bound TGF-␤, as previously demonstrated in a study of low-dose induced airway tolerance and in peptide intranasal immunotherapy (27,44). IL-12 was inefficient in breaking tolerance induction in our model.…”

Section: Discussionsupporting

confidence: 74%

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: Discussionsupporting

confidence: 74%

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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“…Dominant T cell epitopes of different allergens and in different combinations have been investigated for intranasal application, resulting in reduction of allergen-specific IgE and IgG responses. However, allergen-specific isotypes are not completely eliminated and only short-term follow up was reported in these models (Hufnagl et al 2005(Hufnagl et al , 2008Marazuela et al 2008;Wild et al 2007). Involvement of Tregs and a Th2 to Th1 shift are important mechanisms in these protocols (Hufnagl et al 2008;Marazuela et al 2008;Winkler et al 2006).…”

Section: Induction Of Tolerance Via the Mucosal Routementioning

confidence: 98%

Cell-Based Therapy in Allergy

Baranyi

Gattringer

Valenta

et al. 2011

Vaccines Against Allergies

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IgE-mediated allergy is an immunological disorder occurring in response to otherwise harmless environmental antigens (i.e., allergens). Development of effective therapeutic or preventive approaches inducing robust tolerance toward allergens remains an unmet goal. Several experimental tolerance approaches have been described. The therapeutic use of regulatory T cells (Tregs) and the establishment of molecular chimerism are two cell-based strategies that are of particular interest. Treg therapy is close to clinical application, but its efficacy remains to be fully defined. Recent proof-of-concept studies demonstrated that transplantation of syngeneic hematopoietic stem cells modified in vitro to express a major allergen leads to molecular chimerism and robust allergen-specific tolerance. Here we review cell-based tolerance strategies in allergy, discussing their potentials and limitations.

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“…Importantly, transfer of CD4+ T cells from OVA-tolerized animals prevented subsequent allergen sensitization and allergic airway disease in naive recipients. Therefore, in the present model allergen-specific mucosal tolerance induction was a function of regulatory CD4+ T cells producing high levels of IL-10 [20]. …”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharides Modulate Allergen-Specific Immune Regulation in a Murine Model of Mucosal Tolerance Induction

Gerhold

Avagyan

Reichert

et al. 2008

Int Arch Allergy Immunol

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Background: Farming has been widely reported to be associated with decreased risk of developing atopic disorders, but underlying immunomodulatory mechanisms are still not fully defined. We delineated T-cell functions after induction of mucosal tolerance in the context of intranasally delivered organic dust compounds, lipopolysaccharides (LPS). Methods: BALB/c mice were pretreated intranasally with ovalbumin (OVA) with or without LPS (Escherichia coli) three times (days –21, –14, –7) prior to systemic OVA sensitization (days 1 and 14) and airway allergen challenges (days 28–30). CD4+ spleen T cells from pretreated and sensitized donors were characterized for cytokine function, and transferred into naive recipients prior to subsequent OVA sensitization and challenges. Results: Intranasal OVA pretreatment suppressed Th2-mediated immune and inflammatory responses and enhanced frequency of regulatory T cells in OVA-sensitized and -challenged mice. Addition of LPS to OVA, but not LPS alone, inhibited development of allergen-induced sensitization and eosinophilic airway infiltration, and markedly enhanced allergen-specific IgG1 serum levels and frequencies of IL-10- and IFN-γ-producing CD4+ T cells. Transfer of CD4+ spleen T cells from OVA-pretreated animals protected naive recipients against subsequent allergen sensitization and airway disease, whereas transfer from LPS/OVA-pretreated animals only protected against allergen sensitization. Conclusion: Microbial LPS modulated mucosal tolerance by inducing allergen-specific IgG1 production and distinct effector CD4+ T cells with a mixed regulatory/Th1 phenotype. Organic dust components such as LPS might therefore be important immune modulators in naturally occurring or preventive allergen-specific tolerance induction.

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Intranasal tolerance induction with polypeptides derived from 3 noncross-reactive major aeroallergens prevents allergic polysensitization in mice

Cited by 37 publications

References 38 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

Cell-Based Therapy in Allergy

Lipopolysaccharides Modulate Allergen-Specific Immune Regulation in a Murine Model of Mucosal Tolerance Induction

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