Studies of vaccine adjuvants that can elicit the generation of mucosal immune responses to cutaneously delivered antigens

Vaccines are designed to protect against infectious diseases. The majority of commercially available vaccines are administered to hosts via parenteral routes and provoke the development of only systemic immunity. However, most pathogens infect susceptible hosts by crossing a mucosal barrier. The development of vaccines capable of eliciting both systemic and mucosal immune responses would be desirable, and provide better protection to immunized hosts. Our laboratory previously reported that the bioactive form of vitamin D3, la25(OH)2D3, when added to vaccines and administered cutaneously, induces both systemic and mucosal immune responses. It was established that antigen-laden dendritic cells (DCs) can bypass draining lymph node (LN) sequestration and localize to classical inductive sites of mucosal immunity when exposed to la25(OH)2D3 during their maturation. In Chapter 2 of this thesis, we demonstrate that la25(OH)2D3-exposed skin residing DCs can bypass the draining LN and localize to various non-draining LNs and Peyer's patches (PPs). The responsible mechanism involves a temporal suppression in the activation-induced upregulation of CCR7, resulting in a depressed chemotaxis toward CCL21 (a ligand for CCR7). The suppression is transient and normal chemotactic activities are required over time. Pathogen recognition is achieved in part through Toll-like receptors (TLRs) that are members of the pattern-recognition receptor family. Innate immune responses that are initiated by TLR activation can influence subsequent events and regulate the types of adaptive immune responses that develop. In Chapter 3 of this thesis, natural ligands for TLR3, TLR4 and TLR9 were examined for possible roles as adjuvants in the generation of systemic and mucosal immune responses. DCs activated with TLR3 or TLR4 ligands were able to upregulate the expression of 25-hydroxycholecalciferol-la-hydroxylase, an enzyme that catalyzes the conversion of bioinactive 25-hydroxyvitamin D3 to the active la25(OH)2D3. Also, TLR3/4-activated DCs exhibited altered migratory properties in vivo through a la25(OH)2D3 -dependent processes. Our results suggest that the successful generation of mucosal immunity to antigens administered cutaneously, might best be achieved when endogenously produced, or exogenously administered lot25(OH)2D3, is available.