Adjuvanticity of the oil-in-water emulsion MF59 is independent of Nlrp3 inflammasome but requires the adaptor protein MyD88

Seubert, Anja; Calabrό, Samuele; Santini, Laura; Galli, Barbara; Genovese, Alessia; Valentini, Sara; Aprea, Susanna; Colaprico, Annalisa; D’Oro, Ugo; Giuliani, Marzia M.; Pallaoro, Michele; Pizza, Mariagrazia; O’Hagan, Derek T.; Wack, Andreas; Rappuoli, Rino; Gregorio, Ennio De

doi:10.1073/pnas.1107941108

Cited by 160 publications

(141 citation statements)

References 32 publications

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“…A possible explanation for this finding is that with lupus-associated autoantigens, adjuvanticity is provided by endosomal TLR engagement by selfnucleic acids, whereas adjuvanticity of complete (CFA) and incomplete (IFA) Freund's adjuvants, or alum in response to conventional exogenous antigens is mediated by endosomal TLRindependent pathways (46)(47)(48).…”

Section: Discussionmentioning

confidence: 99%

Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus

Baccalà¹,

Gonzalez-Quintial²,

Blasius

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

120

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In vitro evidence suggests that plasmacytoid dendritic cells (pDCs) are intimately involved in the pathogenesis of lupus. However, it remains to be determined whether these cells are required in vivo for disease development, and whether their contribution is restricted to hyperproduction of type I IFNs. To address these issues, we created lupus-predisposed mice lacking the IFN regulatory factor 8 (IRF8) or carrying a mutation that impairs the peptide/histidine transporter solute carrier family 15, member 4 (SLC15A4). IRF8-deficient NZB mice, lacking pDCs, showed almost complete absence of anti-nuclear, anti-chromatin, and anti-erythrocyte autoantibodies, along with reduced kidney disease. These effects were observed despite normal B-cell responses to Toll-like receptor (TLR) 7 and TLR9 stimuli and intact humoral responses to conventional T-dependent and -independent antigens. Moreover, Slc15a4 mutant C57BL/6-Fas lpr mice, in which pDCs are present but unable to produce type I IFNs in response to endosomal TLR ligands, also showed an absence of autoantibodies, reduced lymphadenopathy and splenomegaly, and extended survival. Taken together, our results demonstrate that pDCs and the production of type I IFNs by these cells are critical contributors to the pathogenesis of lupus-like autoimmunity in these models. Thus, IRF8 and SLC15A4 may provide important targets for therapeutic intervention in human lupus.E xtensive evidence suggests that type I IFNs are major pathogenic effectors in lupus-associated systemic autoimmunity. A well-documented pattern of expression of type I IFN-inducible genes occurs in peripheral blood mononuclear cells of patients with systemic lupus erythematosus (SLE) (1-3), and reduced disease is observed in some lupus-predisposed mice that either lack the common receptor (IFNAR) for these cytokines (4, 5) or have been treated with IFNAR-blocking antibody (6). Consequently, attention has focused on defining the cell subsets and signaling processes involved in type I IFN production, the mechanisms by which these mediators accelerate disease, and approaches to interfere with these pathogenic events.Early in vitro studies showed that type I IFN production can be induced in normal blood leukocytes by SLE autoantibodies complexed with nucleic acid-containing apoptotic/necrotic cell material, and further work demonstrated that this activity is sensitive to RNase and DNase digestion (7,8). These results were integrated in a more comprehensive scheme following the demonstration that type I IFN induction by these complexes is mediated by the engagement of endosomal Toll-like receptors (TLRs) (9-11). Similarly, antigenic cargo containing nucleic acids was found to promote B-cell proliferation in a TLR9-or TLR7-dependent manner, with this effect enhanced by type I IFN signaling (9, 12, 13). The contribution of nucleic acid-sensing TLRs to systemic autoimmunity was further corroborated by studies in lupus-predisposed mice lacking or overexpressing TLR7 and/or TLR9 (14-20), and in Unc93b1 (3d) mutant mice i...

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Section: Discussionmentioning

confidence: 99%

Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus

Baccalà¹,

Gonzalez-Quintial²,

Blasius

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

120

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“…These adjuvants stimulate local inflammatory responses at the injection site, which lead to leukocyte recruitment, antigen transport to draining lymph nodes, and APC activation (17). In preclinical models, adjuvants like MF59 appear to stimulate lymphocyte priming through a TLR-independent MyD88-dependent pathway (18) and subsequent Th2-mediated antibody responses (19), whereas the majority of helper CD4 T cells induced in people are biased to a Th0/Th1 phenotype (20,21). A separate strategy for inducing anti-viral Th1 responses involves activation of TLR4, which is unique among the TLR family in its ability to activate MyD88 and IFN production through the TRIF pathway (8).…”

Section: Discussionmentioning

confidence: 99%

Adjuvant solution for pandemic influenza vaccine production

Clegg

Roque

Hoeven

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Extensive preparation is underway to mitigate the next pandemic influenza outbreak. New vaccine technologies intended to supplant egg-based production methods are being developed, with recombinant hemagglutinin (rHA) as the most advanced program for preventing seasonal and avian H5N1 Influenza. Increased efforts are being focused on adjuvants that can broaden vaccine immunogenicity against emerging viruses and maximize vaccine supply on a worldwide scale. Here, we test protection against avian flu by using H5N1-derived rHA and GLA-SE, a two-part adjuvant system containing glucopyranosyl lipid adjuvant (GLA), a formulated synthetic Toll-like receptor 4 agonist, and a stable emulsion (SE) of oil in water, which is similar to the best-in-class adjuvants being developed for pandemic flu. Notably, a single submicrogram dose of rH5 adjuvanted with GLA-SE protects mice and ferrets against a high titer challenge with H5N1 virus. GLA-SE, relative to emulsion alone, accelerated induction of the primary immune response and broadened its durability against heterosubtypic H5N1 virus challenge. Mechanistically, GLA-SE augments protection via induction of a Th1-mediated antibody response. Innate signaling pathways that amplify priming of Th1 CD4 T cells will likely improve vaccine performance against future outbreaks of lethal pandemic flu.

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“…It is widely accepted that alum acts as an adjuvant to activate the intracellular stress sensor inflammasomes [28,29] and ROS are required for inflammasome activation [30]. However, the critical role of alum as an adjuvant to activate inflammasomes has been controversial, as alum can exert adjuvanticity also in mice deficient of inflammasomes [31,32]. A recent study revealed that alum-induced adjuvant effects are dependent on inducible heat shock protein 70 (hsp70) [33].…”

Section: Discussionmentioning

confidence: 99%

Exposure to inhomogeneous static magnetic field beneficially affects allergic inflammation in a murine model

Csillag

Kumar

Szabó

et al. 2014

J. R. Soc. Interface.

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Previous observations suggest that static magnetic field (SMF)-exposure acts on living organisms partly through reactive oxygen species (ROS) reactions. In this study, we aimed to define the impact of SMF-exposure on ragweed pollen extract (RWPE)-induced allergic inflammation closely associated with oxidative stress. Inhomogeneous SMF was generated with an apparatus validated previously providing a peak-to-peak magnetic induction of the dominant SMF component 389 mT by 39 T m 21 lateral gradient in the in vivo and in vitro experiments, and 192 mT by 19 T m 21 in the human study at the 3 mm target distance. Effects of SMF-exposure were studied in a murine model of allergic inflammation and also in human provoked skin allergy. We found that even a single 30-min exposure of mice to SMF immediately following intranasal RWPE challenge significantly lowered the increase in the total antioxidant capacity of the airways and decreased allergic inflammation. Repeated (on 3 consecutive days) or prolonged (60 min) exposure to SMF after RWPE challenge decreased the severity of allergic responses more efficiently than a single 30-min treatment. SMF-exposure did not alter ROS production by RWPE under cell-free conditions, while diminished RWPEinduced increase in the ROS levels in A549 epithelial cells. Results of the human skin prick tests indicated that SMF-exposure had no significant direct effect on provoked mast cell degranulation. The observed beneficial effects of SMF are likely owing to the mobilization of cellular ROS-eliminating mechanisms rather than direct modulation of ROS production by pollen NAD(P)H oxidases.

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Adjuvanticity of the oil-in-water emulsion MF59 is independent of Nlrp3 inflammasome but requires the adaptor protein MyD88

Cited by 160 publications

References 32 publications

Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus

Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus

Adjuvant solution for pandemic influenza vaccine production

Exposure to inhomogeneous static magnetic field beneficially affects allergic inflammation in a murine model

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