Journal
JOURNAL OF CONTROLLED RELEASE
Volume 266, Issue -, Pages 87-99Publisher
ELSEVIER
DOI: 10.1016/j.jconrel.2017.09.020
Keywords
Dendritic cell targeting; C type lectin receptors; Mannan; Skin vaccination; Laser microporation; Epicutaneous immunization; Hypoallergen; Specific immunotherapy
Funding
- Allergy-Cancer-BioNano Research Centre of the University of Salzburg
- PhD program Immunity in Cancer and Allergy - Austrian Science Fund (FWF) [W 1213]
- European Research Council (ERCAdvanced) [339977]
- Anniversary Fund of the Oesterreichische Nationalbank (OeNB) [15941]
- Trans4tech funding of the Government of the region of Salzburg [20102-P1509072-T4T01-2015]
- European Research Council (ERC) [339977] Funding Source: European Research Council (ERC)
- Austrian Science Fund (FWF) [W1213] Funding Source: Austrian Science Fund (FWF)
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Due to its unique immunological properties, the skin is an attractive target tissue for allergen-specific immunotherapy. In our current work, we combined a dendritic cell targeting approach with epicutaneous immunization using an ablative fractional laser to generate defined micropores in the upper layers of the skin. By coupling the major birch pollen allergen Bet v 1 to mannan from S. cerevisiae via mild periodate oxidation we generated hypoallergenic Bet-mannan neoglycoconjugates, which efficiently targeted CD14(+) dendritic cells and Langerhans cells in human skin explants. Mannan conjugation resulted in sustained release from the skin and retention in secondary lymphoid organs, whereas unconjugated antigen showed fast renal clearance. In a mouse model, Bet-mannan neoglycoconjugates applied via laser-microporated skin synergistically elicited potent humoral and cellular immune responses, superior to intradermal injection. The induced antibody responses displayed IgE-blocking capacity, highlighting the therapeutic potential of the approach. Moreover, application via micropores, but not by intradermal injection, resulted in a mixed TH1/TH17-biased immune response. Our data clearly show that applying mannan-neoglycoconjugates to an organ rich in dendritic cells using laser-microporation is superior to intradermal injection. Due to their low IgE binding capacity and biodegradability, mannan neoglycoconjugates therefore represent an attractive formulation for allergen-specific epicutaneous immunotherapy.
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