Host Defense Peptides

Host defense peptides (HDPs), also called cationic antimicrobial peptides, are another example of innate immune stimulators. These molecules are found in virtually every life form and can be grouped as defensins and cathelicidins. HDPs are fundamental components of the innate immune response.^5,20 Their wide spectrum of functions includes direct antimicrobial activities, immunostimulatory functions of both innate and acquired immunity, and involvement in wound healing, cell trafficking, and vascular growth.^21–23 The antimicrobial activities of HDPs have been known for a long time, but recent evidence suggests that under physiological concentrations the immunomodulatory functions of mammalian HDPs outbalance the direct antimicrobial activities. These functions can include the recruitment of immature dendritic cells and T-cells, glucocorticoid production, macrophage phagocytosis, mast cell degranulation, complement activation, and interleukin-8 production by epithelial cells.^24–26 HDPs also have been shown to up-regulate gene expression in epithelial cells and monocytes, and neutralization of pro-inflammatory cytokine induction and lethality in response to lipopolysaccharide/endotoxin.^{5, 27–34} Moreover, recent studies have shown that host defense peptides can also adjuvant vaccines.^35–39 For example, ovalbumin-specific immune responses were enhanced after intranasal co-administration of ovalbumin and the human neutrophil peptides 1–3. The fusion of the gene encoding the murine beta-defensin 2 to the gene encoding the human immunodeficiency virus glycoprotein 120 resulted in not only stronger but also mucosal immune responses in immunized mice.^35,38,39 Other examples include B-cell lymphoma vaccines, which were enhanced by fusion of the tumor epitope with genes encoding murine beta defensins.³⁶ These examples illustrate that HDPs have been successfully used as adjuvants to enhance vaccine-specific immunity.

Polyphosphazenes

Particulate Delivery Systems

Particle-based delivery of vaccine antigens has proven to be a very effective way of delivery, especially when compared to the delivery of soluble protein antigens. Microparticles can protect the vaccine antigen from degradation while increasing uptake by specialized immune cells such as dendritic cells.⁴⁶ They therefore represent effective ways of delivering vaccines, and large efforts are currently underway to develop effective particulate delivery systems. Microparticles including polymers such as PLGA particles, polyphosphazenes, liposomes, and ISCOMs facilitate phagocytosis by antigen-presenting cells.⁴⁷ Once inside the cell, they release the antigen into the phago-endosome, where it is processed and subsequently loaded onto MHC molecules for antigen-presentation. Pathogen recognition receptors such as TLR9 are present in the same compartment, suggesting the incorporation of CpG DNA as an effective method of stimulating antigen presenting cells. Furthermore, microparticles also facilitate uptake across the mucosal surfaces, which predominantly occurs by M cells which are overlying the Peyer's patches.^48,49 Dendritic cells have been shown to extend their dendrites between epithelial cells to sample antigen in the lumen, but the significance of this pathway for uptake of particles is unclear.⁵⁰ The use of microparticles in the delivery of mucosal vaccines has been modestly successful. However, novel approaches such as targeting to specific cells as well as addition of adjuvants such as CpG ODN or HDPS have the potential to improve the potency of microparticles as delivery vehicles for the induction of mucosal immune responses.⁵¹