Potential adjuvantic properties of innate immune stimuli

Abstract

Just as the prescient comment by Gaston Ramon was relegated to the last footnote of his 1926 paper, 1 so has research on the mechanisms of action of adjuvants, until recently, languished as parenthetical annotations and addenda in the archives of immunology and vaccine development. Ramon defined immunological adjuvants as "substances used in combination with a specific antigen that produced a more robust immune response than the antigen alone." Interestingly enough, he was referring to his empirical findings that the addition of bread crumbs, tapioca, saponin and 'starch oil' to antigenic preparations greatly enhanced antibody responses to diphtheria or tetanus. 2 A year later, the adjuvanticity of aluminum salts (primarily phosphate and hydroxide) was discovered by Glenny and coworkers. 3 In the 83 years that have elapsed, the repertoire of investigational adjuvants has grown to encompass a very wide range of materials, 4 but aluminum salt-based mineral salts (generically, and incorrectly, termed "alum") have remained the only adjuvants currently approved by the FDA. Aluminum salts have enjoyed a good safety record, but they are weak adjuvants for antibody induction and induce a T helper-2 (T H 2)-skewed, rather than a T helper-1 (T H 1) response. 5,6 Furthermore, not only are aluminum salts ineffective at inducing cytotoxic T lymphocyte (CTL) or mucosal IgA antibody responses, but also have a propensity to induce IgE responses, which have been associated with allergic reactions in some subjects. 5,6 Very recent reports implicate the Nalp3 inflammasome, a component of the innate immune response, as the effector limb of alum-associated adjuvanticity. [7][8][9] In 1962, Dresser observed that injection of purified soluble proteins not only failed to stimulate an immune response, but tolerized animals unless a bacterial extract was admixed with the protein immunogen. 10 This led him to redefine adjuvanticity as "a property of a substance which can act as a physiological switch, directing at least some immunologically competent cells to respond by making antibody rather than by becoming immunologically paralyzed by the antigen," 11 confirming Johnson's earlier observations that lipopolysaccharide (LPS) from Gram-negative bacteria exerted potent adjuvant properties, 12 and perhaps paved the way for the subsequent discovery of the wide range of microorganism-derived adjuvants. 13 TLRs are pattern recognition receptors present on diverse cell types that recognize specific molecular patterns present in molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). 14,15 There are 10 TLRs in the human genome;

Modulation of γδ T cell responses by TLR ligands

“…TLR agonists including natural TLR ligands or synthetic analogues of natural TLR ligands offer a therapeutic potential for treatment of cancer, infectious diseases, and type I allergy or as vaccine adjuvant [29,30]. TLR antagonists bind to TLR but inhibit the biological activity of the respective TLR [e.g., TLR4 antagonist, lipopolysaccharide (LPS) from R. sphaeroides or TLR9 antagonist, oligonucleotide (ODN)-TTAGGG].…”

“…Neutralizing anti-TLR2 Ab T2.5 combined with anti-TLR4/MD-2 Ab and antibiotics protected mice against sepsis induced by E. coli or Salmonella enterica [59,60]. An exhaustive examination of available TLR2 agonist and antagonists and the development of new compounds are under investigation [29,30]. MAL, for example, seems to be an attractive therapeutic target for several diseases, because TLR2 requires MAL for the recruitment of MyD88 and thus for TLR2 activation [29].…”

Trends in adjuvant development for vaccines: DAMPs and PAMPs as potential new adjuvants

“…It is interesting to note that while binding of LPS to TLR4 activates both the MyD88-TIRAP and TRIF-TRAM pathways (Figure 2), MPL was shown to activate only the TRIF-TRAM pathway, which accounts for its adjuvant properties and low toxicity (23). Other TLR agonists are also being tested for use as adjuvants, such as immunostimulatory molecules containg repeating sequences of cytosine phosphoguanosine (CpG) dinucleotides targeting TLR9 and the TLR7/8 agonists imiquimod and resiquimod (51).…”

A Novel and Divergent Role of Granzyme A and B in Resistance to Helminth Infection

“…A very early Th1-biased proinflammatory cytokine production by NK and/or T cells is probably stimulated by LPS-like molecules (22) from the filarial endosymbiont Wolbachia, present in L3 and known to induce proinflammatory cytokines (13).…”