Adjuvants modulating mucosal immune responses or directing systemic responses towards the mucosa

Abstract

-In developing veterinary mucosal vaccines and vaccination strategies, mucosal adjuvants are one of the key players for inducing protective immune responses. Most of the mucosal adjuvants seem to exert their effect via binding to a receptor/or target cells and these properties were used to classify the mucosal adjuvants reviewed in the present paper: (1) ganglioside receptor-binding toxins (cholera toxin, LT enterotoxin, their B subunits and mutants); (2) surface immunoglobulin binding complex CTA1-DD; (3) TLR4 binding lipopolysaccharide; (4) TLR2-binding muramyl dipeptide; (5) Mannose receptor-binding mannan; (6) Dectin-1-binding ß 1,3/1,6 glucans; (7) TLR9-binding CpG-oligodeoxynucleotides; (8) Cytokines and chemokines; (9) Antigen-presenting cell targeting ISCOMATRIX and ISCOM. In addition, attention is given to two adjuvants able to prime the mucosal immune system following a systemic immunization, namely 1α, 25(OH) 2 D 3 and cholera toxin.

Cholera toxin promotes the generation of semi-mature porcine monocyte-derived dendritic cells that are unable to stimulate T cells

“…Ctx causes increased plasma levels of cAMP through the ADP-ribosyltransferase activity of the A-subunit after binding of the B-subunit to the cell surface via the ubiquitous GM1 ganglioside [2,9,10,46]. Consistent with our observations for Ctx, cAMP-elevating agents can directly increase IL-10 production, inhibit TNFα secretion and MHC-II and CD40 expression, and reduce stimulatory capacity in murine DC [25].…”

“…However, if the nonstimulatory phenotype of Ctx-primed DC was largely caused by lack of TNFα, it seems possible that other cells such as macrophages or epithelial cells would supply pro-inflammatory cytokines in an in vivo situation [10]. Notably, the F4-fimbriae co-administered with Ctx by Verdonck et al [48] also directly act as mucosal antigens with the potential capacity to modulate DC phenotype.…”

“…It can also be used for bait vaccination Cholera toxin (Ctx) is a potent mucosal adjuvant that has been used successfully in a large number of murine studies [10,13,14,29]. Unfortunately, the high toxicity of native Ctx in humans precludes the clinical use of Ctx [32].…”

Bacterial c-di-GMP Is an Immunostimulatory Molecule

“…Bacterial DNA containing unmethylated CpG motifs is also known to stimulate production of polyclonal Ig and Th1-associated immunomodulatory cytokines including IFN-␥, IL-12, and TNF-␣, which provide some protection against intracellular pathogens (39 -41). CpGcontaining oligodeoxynucleotides, which act as TLR9 agonists, are recognized as adjuvants modulating mucosal immune responses (57). Like CpG, c-di-GMP itself can stimulate an immune response; however, the immunostimulatory ability of c-di-GMP is TLR independent.…”

A new concept to stimulate mucosal as well as systemic immunity by parenteral vaccination as applied to the development of a live attenuatedSalmonella entericaserovar Dublin vaccine

“…This often results in faecal shedding of vaccine organisms and undesirable clinical signs such as fever and diarrhoea [29,32,39]. Various antigen delivery and mucosal immunity stimulation methods, such as particulated and non-particulated adjuvants, have been studied [8,11]. For ruminants, encapsulation of vaccine antigens in microparticles has been considered an efficient oral delivery method to stimulate intestinal mucosal immunity [3,11].…”