Rewiring biology Targeting dendritic cells to reset allergic disease

In this thesis we have investigated how to innovate allergen immunotherapy (AIT) strategies centered around dendritic cells (DCs) as orchestrators of adaptive immune responses. To that end, we characterized the immunological effects of allergens on DCs and investigated novel therapy candidates. Our data indicate that neither the major HDM allergens Der p 1 and Der p 2, nor the major cat allergen Fel d 1 activate DCs by them-selves. This emphasizes the need for immune-activating and -modulating adjuvants in AIT. One possibility to overcome this inertness it the concept of plant-produced enveloped bioparticles (eBPs) displaying recombinant allergen on their surface. We have shown that those eBPs lead to a more powerful DC maturation and cytokine response than soluble (or alum-conjugated) allergen. Based on our findings related to the HDM allergen Der p 2, the allergic background shows no major impact on the induced responses towards soluble and particulate allergen. Besides, we have shown that the eBPs reduce basophil degranulation, which suggests hypoallergenicity. Based on those intrinsic auto-adjuvant effects of eBPs, we conclude that allergen-displaying eBPs possibly contribute to safer and faster desensibilisation of patients. Furthermore, we have analyzed the immunomodulatory properties of subcutaneously administered vitamin D3 (VitD3) as a potential tolerance-inducing adjuvant in AIT in a human in vivo setting. While we detected peripheral immune modulations within innate and adaptive responses, those observations were not linked to tolerance-associated signatures. However, it remains important to explore whether VitD3 can trigger tolerogenic responses in an allergen-specific setting.