Epicutaneous Immunotherapy Prevents from Induction of Anaphylaxis to Further Allergens (original) (raw)
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Journal of Allergy and Clinical Immunology, 2014
Background Allergen-specific immunotherapy favours immune deviation from a Th2 to a Th1 response and increases the number of regulatory T cells (Tregs). Epicutaneous immunotherapy (EPIT) of sensitized mice decreases the clinical and the allergen-specific Th2 responses and increases local and peripheral Foxp3 + Tregs. Objective To investigate the role of Tregs in EPIT and characterize their phenotype and maintenance following EPIT. Methods Tregs were investigated using in vivo depletion or adoptive transfer into BALB/c mice. Tregs were depleted using anti-CD25 antibody injection during EPIT, and allergenspecific responses were compared with Sham, EPIT alone and na€ ıve mice. To demonstrate that Tregs can mediate protection by their own, and to study their maintenance following the end of EPIT, CD25 + CD4 + Tregs isolated from mice just after or 8 weeks after EPIT were transferred into peanut-sensitized mice. Foxp3-IRES-mRFP mice were transferred with EPIT-induced Tregs to analyse the induction of host Tregs. Results The anti-CD25 antibody injection to EPIT mice abrogated the induction of Tregs in spleen and the expression of Foxp3 in oesophagus. This resulted in levels of peanutinduced eosinophilic infiltration in oesophagus similar to Sham and significantly higher than EPIT. Whereas the transfer of Tregs from Sham-treated mice demonstrated no effect, the transfer of Tregs isolated just after EPIT prevented peanut-induced eosinophil infiltration and eotaxin expression and induced Foxp3 in oesophagus. The transfer of Tregs isolated 8 weeks after EPIT suppressed allergen-specific responses as efficiently as did Tregs isolated just after EPIT and increased spleen Foxp3 + CD25 + CD4 + cells similarly. The use of reporter mice demonstrated an increase in host Tregs. Conclusions These results confirm the Tregs-mediated mechanism of EPIT and demonstrate the persistence of efficient Tregs during a long period of time after treatment cessation. This suggests that EPIT induces long-term tolerance in peanut-sensitized mice.
Specific epicutaneous immunotherapy prevents sensitization to new allergens in a murine model
Journal of Allergy and Clinical Immunology, 2015
Background: Allergy to cow's milk increases the risk of sensitization to other foods in young children. Objectives: We sought to evaluate the effect of early epicutaneous immunotherapy (EPIT) on further sensitization to peanut or house dust mite (HDM) in a murine model of sensitization to cow's milk. Methods: BALB/c mice orally sensitized to milk were epicutaneously treated with a Viaskin patch (DBV Technologies) loaded with milk proteins for 8 weeks. Mice were then sensitized to peanut or HDM. After sensitization to peanut, mice were exposed to a peanut regimen known to induce eosinophilic esophageal inflammation. After sensitization to HDM, mice were challenged with aerosols to HDM, and airway hyperresponsiveness was evaluated by using plethysmography. Humoral response was also analyzed. The role of regulatory T (Treg) cells was evaluated by adoptively transferring Treg cells from milk EPIT-treated mice to naive mice before sensitization to peanut. Protection against anaphylaxis was also investigated. Methylation of the promoter region of transcription factors was analyzed by using PCR assays. Results: In milk-sensitized mice specific EPIT prevented further sensitization to peanut or HDM. EPIT significantly modified the humoral response, reduced T H 2 cytokine levels, decreased eosinophilic esophageal infiltration, and suppressed airway hyperresponsiveness. The protective effect was sustained over 2 months. Moreover, the adoptive transfer of milk EPIT Treg cells completely prevented sensitization to peanut and peanutinduced anaphylaxis. Milk EPIT enhanced methylation of the GATA-3 promoter region. Conclusions: Our results showed that EPIT influences the natural history of allergy and reduces the risk of further sensitization through a Treg cell-dependent mechanism. (J Allergy Clin Immunol 2014;nnn:nnn-nnn.)
Cellular & Molecular Immunology, 2016
Allergen-specific immunotherapy has been proposed as an attractive strategy to actively treat food allergy using the following three different immunotherapy routes: oral (OIT), sublingual (SLIT) and epicutaneous (EPIT) immunotherapy. Regulatory T cells (Tregs) have been shown to have a pivotal role in the mechanisms of immunotherapy. The aim of this study was to compare the phenotype and function of Tregs induced in peanut-sensitized BALB/c mice using these three routes of treatment. We show that although EPIT, OIT and SLIT were all able to effectively desensitize peanutsensitized mice, they induced different subsets of Tregs. Foxp3+ Tregs were induced by the three treatment routes but with greater numbers induced by EPIT. EPIT and OIT also increased the level of LAP+ Tregs, whereas SLIT induced IL-10+ cells. The suppressive activity of EPIT-induced Tregs did not depend on IL-10 but required CTLA-4, whereas OIT acted through both mechanisms and SLIT was strictly dependent on IL-10. Moreover, the three routes influenced the homing properties of induced Tregs differently, with a larger repertoire of chemokine receptors expressed by EPIT-induced Tregs compared with OIT-and SLIT-induced cells, resulting in different protective consequences against allergen exposure. Furthermore, whereas OIT-or SLIT-induced Tregs lost their suppressive activities after treatment was discontinued, the suppressive activities of EPIT-induced Tregs were still effective 8 weeks after the end of treatment, suggesting the induction of a more long-lasting tolerance. In summary, EPIT, OIT and SLIT mediated desensitization through the induction of different subsets of Tregs, leading to important differences in the subsequent protection against allergen exposure and the possible induction of tolerance.
Clinical & Experimental Allergy, 2011
Background Recent studies have implicated CD4 1 CD25 1 regulatory T cells (nTregs) in the maintenance of tolerance to oral antigens and in the regulation of the food allergic IgE response. Objective The objective was to assess if nTregs can transfer allergen-specific oral tolerance to naïve, non-TCR transgenic mice and regulate peanut extract (PE)-specific hypersensitivity responses. Additionally, the role of the regulatory cytokines IL-10 and TGF-b in the modulation of peanut-allergic sensitization was studied. Methods CD25-enriched T cells from PE-tolerant mice were adoptively transferred to recipient mice, which were subsequently sensitized to PE. Depletion of CD25 1 cells and neutralization of IL-10 and TGF-b were compared in a CH3/HeOuJ mouse model of peanut-allergic sensitization. Results Transfer of CD25 1 Tregs-enriched cell populations did not affect the PE-specific cytokine production or PE-specific antibody levels compared with control mice but interestingly resulted in a decrease of mast cell responsiveness. On the contrary, transfer of CD25 1 Tregs-depleted cells caused an increase in non-specific cytokine production, in the absence of changes in PE-specific responses. TGF-b neutralization resulted even in a larger increase in spontaneous release of all cytokines measured (IL-4, IL-5, IL-10, IL-13, and IFN-g), but surprisingly also to a higher PE-specific Th2-associated (IL-4, IL-5, IL-13) cytokine production compared with depletion of CD25 cells or neutralization of IL-10. Similarly, depletion of CD25 cells and TGF-b neutralization but not of IL-10 neutralization lead to an increase in PEspecific antibody levels and elevated mast cell degranulation following a PE challenge. Conclusions and Clinical Relevance We conclude that CD4 1 CD25 1 Tregs from nontransgenic-tolerant mice cannot transfer specific oral tolerance of exogenous antigens to naïve mice and are more involved in general immune suppressive mechanisms. However, we found evidence that TGF-b secreting Tregs (Th3) may play an important role.
T.121. Epicutaneous Immunotherapy (EPIT): Proof of Concept with Various Allergens in Sensitized Mice
Clinical Immunology, 2009
Background Allergen-specific immunotherapy, subcutaneous immunotherapy (SCIT) or oral, has been used for almost a century to redirect inappropriate immune responses in atopic patients. A new mode of administration through the intact skin [epicutaneous immunotherapy (EPIT)], using an original epicutaneous delivery system, may represent an alternative to these classical methods.
Allergy, 2018
Epicutaneous immunotherapy (EPIT) is a promising method for treating food allergies. In animal models, EPIT induces sustained unresponsiveness and prevents further sensitization mediated by Tregs. Here, we elucidate the mechanisms underlying the therapeutic effect of EPIT, by characterizing the kinetics of DNA methylation changes in sorted cells from spleen and blood and by evaluating its persistence and bystander effect compared to oral immunotherapy (OIT). BALB/c mice orally sensitized to peanut proteins (PPE) were treated by EPIT using a PPE-patch or by PPE-OIT. Another set of peanut-sensitized mice treated by EPIT or OIT were sacrificed following a protocol of sensitization to OVA. DNA methylation was analysed during immunotherapy and 8 weeks after the end of treatment in sorted cells from spleen and blood by pyrosequencing. Humoral and cellular responses were measured during and after immunotherapy. Analyses showed a significant hypermethylation of the Gata3 promoter detectable...
The American Journal of Pathology, 2005
Despite structural and functional differences between the initial sites of contact with allergens in the gastrointestinal and nasal tracts, few animal models have examined the influence of the mucosal routes of sensitization on host reactivity to food or environmental antigens. We compared the oral and nasal routes of peanut sensitization for the development of a mouse model of allergy. Mice were sensitized by administration of peanut proteins in the presence of cholera toxin as adjuvant. Antibody and cytokine responses were characterized, as well as airway reactivity to nasal challenge with peanut or unrelated antigens. Oral sensitization promoted higher levels of IgE, but lower IgG responses, than nasal sensitization. Both orally and nasally sensitized mice experienced airway hyperreactivity on nasal peanut challenge. The peanut challenge also induced lung eosinophilia and type 2 helper T-cell-type cytokines in orally sensitized mice. In contrast, peanut challenge in nasally sensitized mice promoted neutrophilia and higher levels of lung MAC-1 ؉ I-A b low cells and inflammatory cytokines. In addition, nasal but not oral, sensitization promoted lung inflammatory responses to unrelated antigens. In summary, both oral and nasal peanut sensitization prime mice for airway hyperreactivity, but the initial mucosal route of sensitization influences the nature of lung inflammatory responses to peanut and unrelated allergens. The prevalence of peanut allergy has doubled in the last decade, and it now affects more than 3 million individuals in the United States. 1 This health care problem is further enhanced by potential cross-reactive allergens. Thus, clinical symptoms were reported in peanut allergic patients who had ingested food of the same botanical family 2-4 or even taxonomically unrelated products. 5 Allergic respiratory symptoms have also been described in peanut-allergic patients after inhalation of airborne peanut particles in school 5 or on airline flights. In this regard, food allergens are now well recognized to play a significant role as aeroallergens in the etiology of asthmatic symptoms in individuals with food allergies. Sensitization to food allergens such as peanut generally occurs in the gastrointestinal (GI) tract. However, it could also occur as a consequence of direct or crosssensitization by inhalational exposure to peanut or crossreactive environmental antigens. For example, peanut allergy is frequently associated with pollen allergy, 9 -12 and peanut allergens share sequence homologies with environmental antigens. 13 A study on children with a history of at least one acute allergic reaction showed that initial reactions to peanut occurred at 24 months of age, with the large majority resulting from a first oral exposure. 5 Because IgE-mediated allergic reactions require prior exposure to the allergen, one cannot rule out earlier sensitization through inhalation of airborne peanut particles. In addition, the presence of cross-reactive IgE to pollen and peanut antigens in pollen-allergic patients 14 and the reports that these individuals can develop positive skin tests to peanut 15,16 suggest that allergic symptoms to peanut may also be caused by respiratory sensitization with cross-reactive allergens. Structural and functional differences have been described between the gut-associated lymphoid tissues and the nasopharyngeal-associated lymphoid tissues 17 that are the first sites