An untold tale of tolerance Conditioning dendritic cells to restore immune balance using tolerogenic nanocarriers

Chronic inflammatory disorders, including various autoimmune diseases and allergies, put a significant burden on our societies. As these conditions stem from a breach in immune tolerance, immune modulation could provide novel avenues for disease prevention or cure. Dendritic cells (DCs) are specialized immune cells that can effectively induce the development of regulatory T cells (Tregs), critical adaptive immune cells for dampening inflammation. Both active metabolites of vitamin D3 (VD3) and retinoic acid (RA) can induce tolerogenic DCs, subsequently fostering a Treg response in vitro. Nanocarriers, such as liposomes or plant-based bioparticles, can be used to combine VD3 or RA with autoantigens or allergens and target these factors simultaneously to DCs in tissue to achieve disease-specific tolerance in vivo. In this thesis, we embarked upon developing a nanocarrier-based vaccine product for future in vivo modulation of DCs. We established negatively charged liposomes as most suitable for administering adjuvants to DCs. We found that various subsets of DCs treated with VD3 or RA, in soluble or liposome-loaded form, induced the development of CD4+ but also CD8+ Tregs in vitro. Furthermore, we established an activating yet hypo-allergenic effect of peanut allergen-loaded bioparticles on DCs. Finally, we present a randomized controlled phase I clinical trial examining the peripheral immune effect of subcutaneous VD3 administration in birch pollen allergic patients. Thus, this thesis encompasses the first steps toward a putative DC-targeted vaccine treating chronic inflammation.