Alum adjuvanticity: Unraveling a century old mystery

Gregorio, Ennio De; Tritto, Elaine; Rappuoli, Rino

doi:10.1002/eji.200838648

Cited by 196 publications

(119 citation statements)

References 26 publications

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“…There was a further significant increase in the number of these cells in the group of mice that received alum + ovalbumin. These results concur with the well established fact that alum when injected with an antigen is a potent adjuvant that induces a Th2 response leading to the production of IL-4 [1,[4][5][6][7].…”

Section: Discussionsupporting

confidence: 90%

“…Adsorption of antigen to alum is essential to enhance its immunogenicity [3]. Alum induces mainly a type-2 immune response that promotes production of IL-4, IgE and IgG1 antibodies [1,[4][5][6][7]. IL-4 secretion, caspase-1 activation, induction of certain chemokines, and complement activation by alum are all factors contributing to the type-2 immune response produced [1].…”

Section: Introductionmentioning

confidence: 99%

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Uric Acid; a Possible Mediator of the Adjuvant Effect of Alum in Mice Immunized with Ovalbumin

Al-Akl¹,

Chakhtoura²,

Kazzi³

et al. 2011

WJV

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Uric Acid; a Possible Mediator of the Adjuvant Effect of Alum in Mice Immunized with Ovalbumin

Al-Akl¹,

Chakhtoura²,

Kazzi³

et al. 2011

WJV

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“…Whereas there is a general consensus about the optimal cytokine milieu for protective immunization, 21,22 aluminum hydroxide-associated T H 2 responses. 26,27 Recently, we showed that the TLR7 ligand 9-benzyl-2-butoxy-8-hydroxyadenine redirects pathogenic allergen-specific T H 2 into T H 1 lymphocytes both in vitro and in vivo. 16,17 In this study we reasoned that the chemical conjugation between an allergen and a 8-OH modified adenine as an adjuvant, instead of a mixture of the 2 components, might further improve the vaccine construct by reducing systemic exposure, targeting appropriate APCs, and inducing a more effective immunomodulation.…”

Section: Discussionmentioning

confidence: 99%

A novel allergen-adjuvant conjugate suitable for specific immunotherapy of respiratory allergy

Filì¹,

Vultaggio²,

Cardilicchia³

et al. 2013

Journal of Allergy and Clinical Immunology

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Background: Several approaches to find a better adjuvant, focus immunomodulation, and reduce allergenicity are under investigation to improve the efficacy and safety of specific immunotherapy. Objective: We performed an investigation of the in vitro and in vivo effects of a purified allergen chemically conjugated to a novel 8-OH modified adenine as an adjuvant. Methods: Purified group 2 major allergen from house dust mite chemically conjugated to 4-(6-amino-9-benzyl-8-hydroxy-9H-purin-2-ylsulfanyl)-butyric acid succinimidyl ester was analyzed by using mass spectrometry. The adduct (nDer p 2-Conj) was assayed for Toll-like receptor activation on transfected HEK293 cells, stimulation of innate cells, and effects on the functional phenotype of specific T-cell lines and clones by means of flow cytometry, real-time PCR, and expression of T H -related transcription factors. Lung cells and sera of nDer p 2-Conjsensitized C57Bl/6 mice were studied by means of cytology, histology, real-time PCR, and ELISA. Results: nDer p 2-Conj stimulated IL-12 and IFN-a production from monocytes and plasmacytoid dendritic cells, respectively, retaining the ability to trigger Toll-like receptor 7 exclusively, and expanded human allergen-specific lymphocytes with reduced ability to produce T H 2-related cytokines and increased IFN-g levels, as based on GATA-3/T-bet expression. In vivo adduct-sensitized mice exhibited reduced eosinophil infiltration and IL-13 expression in the airways, IFN-g upregulation together with IgE downregulation, and an increase in allergenspecific IgG 2a levels in sera. The conjugate exhibited reduced ability to activate human FcεRI 1 cells without inducing T H 17 cells or autoantibodies.

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“…In addition, alum seems to induce activation of Nlrp3 (Nalp3) inflammasome complex, leading to secretion of pro-inflammatory cytokines. These findings have recently been discussed and commented [46]. Eight days after the second immunisation, the animals were briefly anaesthetised (Isofluran, Baxter Medical AB, Kista, Sweden) and challenged by i.n.…”

Section: Airway Allergy Protocolmentioning

confidence: 98%

Neonatal exposure to staphylococcal superantigen improves induction of oral tolerance in a mouse model of airway allergy

et al. 2009

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The hygiene hypothesis suggests that lack of microbial stimulation in early infancy may lead to allergy, but it has been difficult to identify particular protective microbial exposures. We have observed that infants colonised in the first week(s) of life with Staphylococcus aureus have lower risk of developing food allergy. As many S. aureus strains produce superantigens with T-cell stimulating properties, we here investigate whether neonatal mucosal exposure to superantigen could influence the capacity to develop oral tolerance and reduce sensitisation and allergy. BALB/c mice were exposed to staphylococcal enterotoxin A (SEA) as neonates and fed with OVA as adults, prior to sensitisation and i.n. OVA challenge. Our results show that SEA pre-treated mice are more efficiently tolerised by OVA feeding, as shown by lower lung-cell infiltration and antigen-specific IgE response in the SEA pre-treated mice, compared with sham-treated mice. This was not due to deletion or anergy of lymphocytes by SEA treatment, because the SEA pre-treated mice that were fed with PBS showed similar inflammatory response as the sham-treated PBS-fed mice. Our results suggest that strong T-cell activation in infancy conditions the mucosal immune system and promotes development of oral tolerance.Key words: Allergic sensitisation . Mucosal immunity . Staphylococcal enterotoxin A . Tolerance Supporting Information available online IntroductionAllergies have increased markedly in Western industrialised countries, where they now afflict every third child. Allergies are linked to wealth, good education and small families, observations that have given rise to the hygiene hypothesis, according to which the developing immune system should be exposed to appropriate microbial stimulation in early childhood in order to mature correctly and for allergies to be avoided [1,2]. The hygiene hypothesis is also supported by experimental data. Germ-free animals are less prone to develop oral Ã These author contributed equally to this work. Eur. J. Immunol. 2009. 39: 447-456 DOI 10.1002 Immunomodulation 447 tolerance than animals reared conventionally [3,4]. Oral tolerance is induced by passage of antigens over the gut mucosa, prevents against both Th1-and Th2-dominated immune responses [5] and includes development of Treg [6,7]. Natural thymic-dependent Treg (CD4 1 CD25 hi FoxP3 1 ) are fundamental in protection against autoimmunity, gut inflammation and IgE responses. This cell subset has reduced functional capacity in germ-free animals [8].The strongest T-cell activators known are the ''superantigens'', exotoxins produced by certain pathogenic bacteria such as Staphylococcus aureus. These include staphylococcal enterotoxin A, B, C, D and E, as well as toxic shock syndrome toxin-1. The superantigen binds to the variable part of the TCR and to the MHC class II molecule, thereby ''mimicking'' antigen recognition, which leads to T-cell activation [9][10][11][12]. As many as 10-30% of all T cells can become activated by a certain superantigen compared with o0...

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Alum adjuvanticity: Unraveling a century old mystery

Cited by 196 publications

References 26 publications

Uric Acid; a Possible Mediator of the Adjuvant Effect of Alum in Mice Immunized with Ovalbumin

Uric Acid; a Possible Mediator of the Adjuvant Effect of Alum in Mice Immunized with Ovalbumin

A novel allergen-adjuvant conjugate suitable for specific immunotherapy of respiratory allergy

Neonatal exposure to staphylococcal superantigen improves induction of oral tolerance in a mouse model of airway allergy

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