Microbial PAMPs, such as lipopolysaccharides, single-stranded RNA, and bacterial DNA motifs, bind to a family of PRRs called Toll-like receptors (TLR) on innate immune cells and stimulate antigen processing and presentation [16], [17] and [18]. TLRs are widely expressed on dendritic cells (DC) and other professional APCs such as macrophages and B cells. While some TLRs are expressed on the cell surface and act as sensors for extracellular PAMPs (e.g., lipopolysaccharides), a subset of TLR molecules (TLR3, 7, 8 and 9) are expressed

on endosomal membranes and bind Selleckchem BYL719 nucleic acid-derived molecules, such as single-stranded RNA of viral origin for TLR7 and 8 [19], [20], [21], [22], [23] and [24] and bacterial unmethylated DNA oligonucleotides (ODNs) containing CpG motifs (CpG ODNs) for TLR9 [14], [25], [26], [27] and [28]. TLR ligands of natural and synthetic origin are potent inducers of innate immune responses and have been shown to effectively stimulate the transition from an innate immune response to an adaptive immune Smad inhibitor response. As such, TLR agonists have been Libraries evaluated as potential adjuvants in a variety of applications [4]. To date, only one PRR ligand,

3-O-desacyl-4′-monophosphoryl lipid A (MPL), a TLR4 agonist, has been included as an adjuvant in a FDA- or EMA-licensed vaccine. MPL adsorbed onto alum is utilized in the HPV vaccine Cervarix, licensed in the U.S. and Europe [29], and the hepatitis B vaccine Fendrix, licensed in Europe [30]. Imiquimod, a topically administered TLR7 agonist, has been approved for treatment of genital warts, actinic keratosis, and basal cell carcinoma [31]. Other TLR agonists, such as poly(I:C) (TLR3), imidazoquinolines other than imiquimod (TLR7, 8, or 7/8), and CpG ODNs (TLR9), have failed thus far to enter clinical practice as parenteral adjuvants despite a multitude

of Farnesyltransferase promising data obtained in preclinical and clinical studies [32], [33], [34], [35] and [36]. One of the main reasons for this failure is the delicate balance between the induction of augmented immunogenicity by TLR agonists and safety concerns, which are often related to the generation of systemic inflammatory responses [19], [37], [38] and [39]. Several groups have utilized micro- and nanocarriers, such as virus-like particles, liposomes, and PLGA particles, to encapsulate adjuvants [40], [41] and [42]. Encapsulation of adjuvants reduces systemic exposure of adjuvant and enhances uptake by APCs. Nano-size viruses and particles distribute rapidly to the local draining lymph node where they are taken up by subcapsular macrophages and dendritic cells [41], [43] and [44]. Antigens can also be delivered in particles to target efficient uptake by APCs [36], [41], [45] and [46].