CpG-ODN Shapes Alum Adjuvant Activity Signaling via MyD88 and IL-10

Abstract

Aluminum-containing adjuvants usually referred as Alum are considered as T helper type-2 (Th2) adjuvants, while agonists of toll-like receptors (TLRs) are viewed as adjuvants that favor Th1/Th17 immunity. Alum has been used in numerous vaccine formulations; however, its undesired pro-Th2 adjuvant activity constitutes a caveat for Alum-based vaccines. Combining Alum with TLR-dependent, pro-Th1/Th17 adjuvants might dampen the pro-Th2 activity and improve the effectiveness of vaccine formulations. Here, using the ovalbumin (OVA) model of allergic lung inflammation, we found that sensitization with the synthetic TLR9 agonist, which is composed of oligodeoxynucleotides containing CpG motifs adsorbed to Alum, inhibited the development of OVA-induced lung allergic Th2 responses without shifting toward a Th1 pattern. The conversion of T cell immunity from the polarized allergic Th2 response to a non-polarized form by sensitization with OVA/Alum/CpG was dependent on MyD88 signaling in myeloid cells. Notably, sensitization of IL-10-deficient mice with OVA/Alum/CpG resulted in the development of neutrophilic lung inflammation associated with IFNγ production. However, in IL-10/IL-12-deficient mice, it resulted in neutrophilic inflammation dominated by IL-17 production. We conclude that OVA/Alum/CpG sensitization signaling via MyD88 and IL-10 molecules results in non-polarized immunity. Conversely, OVA/Alum/CpG sensitization in presence of MyD88 but absence of IL-10 or IL-10/IL-12 molecules results, respectively, in neutrophilic inflammation associated with IFNγ or IL-17 production. Our work provides novel OVA models of lung inflammation and suggests that Alum/CpG-based formulations might be of potential use in anti-allergic or anti-infectious processes.

TLR9 agonist adsorbed to alum adjuvant prevents asthma-like responses induced by Blomia tropicalis mite extract

“…Since in WT B6 mice, the sensitization with B. tropicalis extract+CpG/Alum does not result in any overt type of airway inflammation and it blocked B. tropicalis ‐specific anaphylactic Abs, we concluded that this type of sensitization prevents the alum's Th2 promoting activities and induces an a nonpolarized cellular immunity. These findings reinforce our previous studies indicating that TLR agonists could be potentially used in formulations of vaccines against allergy . However, it should be noted that depending on the allergen and the TLRs agonists used, different outcomes might occur.…”

“…We have previously shown using the OVA‐asthma model that IL‐10‐deficient mice developed an intense Th1‐like airway inflammation . Therefore, we tested our protocols of B. tropicalis sensitizations and challenge in IL‐10 −/− mice.…”

“…These findings reinforce our previous studies indicating that TLR agonists could be potentially used in formulations of vaccines against allergy. 10,11,16,26 However, it should be noted that depending on the allergen and the TLRs agonists used, different outcomes might occur. For instance, we showed previously that mice sensitized with B. tropicalis/Alum plus bacterial endotoxin developed airway inflam-mation dominated by neutrophils upon B. tropicalis challenges, which was associated with immune-deviation toward Th1/Th17 pattern.…”

“…We have previously shown using the OVA-asthma model that IL-10deficient mice developed an intense Th1-like airway inflammation. 11 Therefore, we tested our protocols of B. tropicalis sensitizations and challenge in IL-10 −/− mice. B. tropicalis/Alum sensitized IL-10 −/− mice developed airway inflammation with infiltration of neutrophils and eosinophils as revealed by total and differential cell counts ( Fig.…”

“…This activity was dependent on MyD88 and IL-10 molecules. 11 Since CpG-ODN was efficient in dampening Th2 activities and it is an adjuvant approved for use in humans, 12 in the present work, we tested whether the adsorption of CpG during the sensitization to B. tropicalis could have a prophylactic effect in preventing B. tropicalis-induced experimental asthma.…”