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New approaches to transcutaneous immunotherapy: targeting dendritic cells with novel allergen conjugates.

Weiss R, Scheiblhofer S, Machado Y, Thalhamer J - Curr Opin Allergy Clin Immunol (2013)

Bottom Line: Furthermore, it covers approaches to generate hypoallergenic conjugates for specific dendritic cell targeting.Coupling of carbohydrates to allergens has been shown to induce formation of nanoparticles, which can specifically target dendritic cells and potentiate immune responses, and by masking B-cell epitopes, can render the molecules hypoallergenic.Due to its abundance of immunocompetent cells, the skin represents an attractive target tissue for novel and enhanced immunotherapeutic approaches.

View Article: PubMed Central - PubMed

Affiliation: Division of Allergy and Immunology, Department of Molecular Biology, University of Salzburg, Salzburg, Austria.

ABSTRACT

Purpose of review: This review summarizes recent preclinical and human studies evaluating allergen-specific immunotherapy via the transcutaneous route, and provides a rationale for the application of modified allergens with reduced allergenicity. Furthermore, it covers approaches to generate hypoallergenic conjugates for specific dendritic cell targeting.

Recent findings: Efficacy and safety of specific immunotherapy by application of allergens to the skin have been demonstrated in both animal models as well as clinical trials. However, localized adverse events have been reported, and delivery of antigens via barrier-disrupted skin has been linked to the induction of unwanted T helper 2-biased immune responses and allergic sensitization. Coupling of carbohydrates to allergens has been shown to induce formation of nanoparticles, which can specifically target dendritic cells and potentiate immune responses, and by masking B-cell epitopes, can render the molecules hypoallergenic.

Summary: Due to its abundance of immunocompetent cells, the skin represents an attractive target tissue for novel and enhanced immunotherapeutic approaches. However, in order to avoid adverse events and therapy-induced sensitizations, transcutaneous immunotherapy requires the use of formulations with reduced allergenic potential. Combining novel hypoallergenic conjugates with painless transcutaneous immunization techniques may provide an efficient and patient-friendly alternative to the standard specific immunotherapy practices.

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Related in: MedlinePlus

Modulating allergenicity of Bet v 1 through carbohydrate coupling. a) IgE-sensitized rat basophil leukemia (RBL) cells were stimulated with increasing concentrations of Bet v 1 coupled to increasing amounts of mannan (mannan:protein w/w ratios of 0.4–2.2). b) Allergenic potential in terms of the IgE cross-linking capacity compared to the wild-type protein, based on the 50%-release log-phase of the Gaussian release curve (EC50 value).
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Figure 2: Modulating allergenicity of Bet v 1 through carbohydrate coupling. a) IgE-sensitized rat basophil leukemia (RBL) cells were stimulated with increasing concentrations of Bet v 1 coupled to increasing amounts of mannan (mannan:protein w/w ratios of 0.4–2.2). b) Allergenic potential in terms of the IgE cross-linking capacity compared to the wild-type protein, based on the 50%-release log-phase of the Gaussian release curve (EC50 value).

Mentions: Our group has recently explored carbohydrate-mediated targeting of allergens to dendritic cells, and its influence on immunogenicity and allergenicity. Protein–carbohydrate complexes of papain and OVA were generated, and their allergenic potential (the capacity to cross-link surface bound IgE), dendritic cell-targeting in vivo and in vitro, and their immunogenicity were assessed [56▪]. We found that coupling carbohydrates to the protein surface can mask B-cell epitopes, thus making the protein ‘hypoallergenic’ (decreased binding and crosslinking of IgE antibodies directed against the native allergen). Interestingly, coupling of either mannan, dextran, or maltodextrin reduced the allergenic potential of papain, but not OVA [56▪]. An explanation for this effect could be the drastically reduced coupling efficiency for OVA at the used carbohydrate/protein ratio, probably leading to less effective shielding of B-cell epitopes. Building on these data, we were able to modulate the allergenic potential of the major birch pollen allergen Bet v 1 by using different protein to carbohydrate ratios (Fig. 2). This clearly indicates that hypoallergenicity of neoglycoconjugates depends on the carbohydrate, the allergen, and also the chemistry employed for the coupling reaction. Finally, we have shown that mannan–protein conjugates were efficiently captured by dendritic cells, both in vitro as well as in vivo (Fig. 3a). Moreover, intradermal immunization of mannan-neoglycoconjugates elicited elevated IgG titers (Fig. 3b) while suppressing de-novo IgE induction, compared with soluble antigen (Fig. 3c) [56▪].


New approaches to transcutaneous immunotherapy: targeting dendritic cells with novel allergen conjugates.

Weiss R, Scheiblhofer S, Machado Y, Thalhamer J - Curr Opin Allergy Clin Immunol (2013)

Modulating allergenicity of Bet v 1 through carbohydrate coupling. a) IgE-sensitized rat basophil leukemia (RBL) cells were stimulated with increasing concentrations of Bet v 1 coupled to increasing amounts of mannan (mannan:protein w/w ratios of 0.4–2.2). b) Allergenic potential in terms of the IgE cross-linking capacity compared to the wild-type protein, based on the 50%-release log-phase of the Gaussian release curve (EC50 value).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3814987&req=5

Figure 2: Modulating allergenicity of Bet v 1 through carbohydrate coupling. a) IgE-sensitized rat basophil leukemia (RBL) cells were stimulated with increasing concentrations of Bet v 1 coupled to increasing amounts of mannan (mannan:protein w/w ratios of 0.4–2.2). b) Allergenic potential in terms of the IgE cross-linking capacity compared to the wild-type protein, based on the 50%-release log-phase of the Gaussian release curve (EC50 value).
Mentions: Our group has recently explored carbohydrate-mediated targeting of allergens to dendritic cells, and its influence on immunogenicity and allergenicity. Protein–carbohydrate complexes of papain and OVA were generated, and their allergenic potential (the capacity to cross-link surface bound IgE), dendritic cell-targeting in vivo and in vitro, and their immunogenicity were assessed [56▪]. We found that coupling carbohydrates to the protein surface can mask B-cell epitopes, thus making the protein ‘hypoallergenic’ (decreased binding and crosslinking of IgE antibodies directed against the native allergen). Interestingly, coupling of either mannan, dextran, or maltodextrin reduced the allergenic potential of papain, but not OVA [56▪]. An explanation for this effect could be the drastically reduced coupling efficiency for OVA at the used carbohydrate/protein ratio, probably leading to less effective shielding of B-cell epitopes. Building on these data, we were able to modulate the allergenic potential of the major birch pollen allergen Bet v 1 by using different protein to carbohydrate ratios (Fig. 2). This clearly indicates that hypoallergenicity of neoglycoconjugates depends on the carbohydrate, the allergen, and also the chemistry employed for the coupling reaction. Finally, we have shown that mannan–protein conjugates were efficiently captured by dendritic cells, both in vitro as well as in vivo (Fig. 3a). Moreover, intradermal immunization of mannan-neoglycoconjugates elicited elevated IgG titers (Fig. 3b) while suppressing de-novo IgE induction, compared with soluble antigen (Fig. 3c) [56▪].

Bottom Line: Furthermore, it covers approaches to generate hypoallergenic conjugates for specific dendritic cell targeting.Coupling of carbohydrates to allergens has been shown to induce formation of nanoparticles, which can specifically target dendritic cells and potentiate immune responses, and by masking B-cell epitopes, can render the molecules hypoallergenic.Due to its abundance of immunocompetent cells, the skin represents an attractive target tissue for novel and enhanced immunotherapeutic approaches.

View Article: PubMed Central - PubMed

Affiliation: Division of Allergy and Immunology, Department of Molecular Biology, University of Salzburg, Salzburg, Austria.

ABSTRACT

Purpose of review: This review summarizes recent preclinical and human studies evaluating allergen-specific immunotherapy via the transcutaneous route, and provides a rationale for the application of modified allergens with reduced allergenicity. Furthermore, it covers approaches to generate hypoallergenic conjugates for specific dendritic cell targeting.

Recent findings: Efficacy and safety of specific immunotherapy by application of allergens to the skin have been demonstrated in both animal models as well as clinical trials. However, localized adverse events have been reported, and delivery of antigens via barrier-disrupted skin has been linked to the induction of unwanted T helper 2-biased immune responses and allergic sensitization. Coupling of carbohydrates to allergens has been shown to induce formation of nanoparticles, which can specifically target dendritic cells and potentiate immune responses, and by masking B-cell epitopes, can render the molecules hypoallergenic.

Summary: Due to its abundance of immunocompetent cells, the skin represents an attractive target tissue for novel and enhanced immunotherapeutic approaches. However, in order to avoid adverse events and therapy-induced sensitizations, transcutaneous immunotherapy requires the use of formulations with reduced allergenic potential. Combining novel hypoallergenic conjugates with painless transcutaneous immunization techniques may provide an efficient and patient-friendly alternative to the standard specific immunotherapy practices.

Show MeSH
Related in: MedlinePlus