Sialic Acids in the Spotlight: Glycoallergen vaccines for allergen immunotherapy

This thesis investigates the use of glycoconjugates, specifically sialic acid allergen glycoconjugates, as a novel approach to enhance the efficacy of allergen-specific immunotherapy (AIT). We conjugated α2-3 sialic acids to house dust mite allergens (Der p 1 and Der p 2) and a pollen allergen (Phl p 5a), and assessed their effects on immune cell function in both allergic and nonallergic individuals. Chapter 2 reviews strategies targeting tolerance-inducing receptors on dendritic cells (DCs), such as Siglecs, C-type lectin receptors (CLRs), and DEC205, to induce antigen-specific tolerance while minimizing side effects of general immunosuppression. Chapter 3 expands this concept to targeting these receptors on other immune cells and discusses the role of carbohydrates, particularly mannan and sialic acids, in modulating immune responses and inducing tolerance. Chapter 4 demonstrates that Der p 2 conjugated to α2-3 sialic acids limits T-cell activation and Th2 cytokine secretion in polyclonally activated PBMCs from nonallergic individuals. Chapter 5 extends this observation to allergic individuals, showing that glycoconjugate-treated DCs reduce T cell activation and proliferation, promote IL-10 secretion, and decrease Th1 and Th2 effector cells. Chapter 6 explores the induction of Tregs by Der p 2 glycoconjugates, identifying the generation of three Treg subsets and increased expression of tolerance markers. These glycoconjugates also prevent the development of a mixed lymphocyte reaction. Chapter 7 shifts focus to neutrophils, showing that Der p 2 and Phl p 5a glycoconjugates reduce ROS production and degranulation in PMNs. Chapter 8 evaluates the effects of Der p 1 glycoconjugates, demonstrating limited T cell activation but no modulation of Th2 cytokines or Treg responses. Finally, Chapter 9 reviews the findings in the context of current literature and discusses the potential of sialic acid conjugates as safe and effective candidates for enhancing AIT