Treatment of allergic disease with nanoemulsion adjuvant vaccines

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153245/1/all13977_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153245/2/all13977.pd

Intranasal nanoemulsion vaccine confers long‐lasting immunomodulation and sustained unresponsiveness in a murine model of milk allergy

BackgroundImmunotherapy for food allergy requires prolonged treatment protocols and, in most cases, does not lead to durable modulation of the allergic immune response. We have demonstrated an intranasal (IN) nanoemulsion adjuvant that redirects allergen‐specific Th2 responses toward Th1 and Th17 immunity, and protects from allergen challenge after only 2‐4 monthly administrations. Here, we investigate the ability of this technology to provide long‐term modulation of allergy in a murine model of cow’s milk allergy.MethodsSix weeks after sensitization to bovine casein, mice received four, monthly IN immunizations with nanoemulsion formulated with casein. Protection from casein challenge was assessed at 4 and 16 weeks after the final vaccine administration.ResultsThe NE vaccine significantly blunted the physiological responses to allergen challenge, and this effect persisted for at least 16 weeks. The protection from challenge was associated with the suppression of casein‐specific Th2 immunity and induced Th1 and Th17 cytokines as well as induction of IL‐10. Of interest, while immunized animals showed significantly decreased Th2 cytokine responses, cow’s milk‐specific IgE remained elevated in the serum at levels associated with reactivity in control sensitized animals. Protection was associated with suppressed mast cell activation and markedly reduced mast cell infiltration into the small intestine.ConclusionThe sustained unresponsiveness of at least 16 weeks after vaccination suggests that the nanoemulsion vaccine alters the allergic phenotype in a persistent manner different from traditional desensitization, and this leads to long‐term suppressive effects on allergic disease without eliminating serum IgE.This study evaluates the ability of an intranasal nanoemulsion‐based vaccine to induce long‐term modulation of allergic reactions in a mouse model of cow’s milk allergy. Intranasal immunization with nanoemulsion adjuvant suppresses Th2 responses and anaphylaxis. The sustained unresponsiveness of at least 16 weeks after vaccination suggests that the nanoemulsion vaccine alters the allergic phenotype.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154959/1/all14064_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154959/2/all14064.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154959/3/all14064-sup-0003-FigS3.pd

Treatment of allergic disease with nanoemulsion adjuvant vaccines

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153245/1/all13977_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153245/2/all13977.pd

Intranasal delivery of allergen in a nanoemulsion adjuvant inhibits allergen- specific reactions in mouse models of allergic airway disease

BackgroundAtopic diseases are an increasing problem that involve both immediate hypersensitivity reactions mediated by IgE and unique cellular inflammation. Many forms of specific immunotherapy involve the administration of allergen to suppress allergic immune responses but are focused on IgE- mediated reactions. In contrast, the effect of allergen- specific immunotherapy on allergic inflammation is complex, not entirely consistent and not well understood. We have previously demonstrated the ability of allergen administered in a nanoemulsion (NE) mucosal adjuvant to suppress IgE- mediated allergic responses and protect from allergen challenge in murine food allergy models. This activity was associated with decreases in allergen- specific IL- 10 and reductions in allergic cytokines and increases in regulatory T cells.ObjectiveHere, we extend these studies to using 2 distinct models, the ovalbumin (OVA) and cockroach (CRA) models of allergic airway disease, which are based predominantly on allergic inflammation.MethodsAcute or chronic allergic airway disease was induced in mice using ovalbumin and cockroach allergen models. Mice received three therapeutic immunizations with allergen in NE, and reactivity to airway challenge was determined.ResultsTherapeutic immunization with cockroach or OVA allergen in NE markedly reduced pathology after airway challenge. The 2 models demonstrated protection from allergen challenge- induced pathology that was associated with suppression of Th2- polarized immune responses in the lung. In addition, the reduction in ILC2 numbers in the lungs of allergic mice along with reduction in epithelial cell alarmins, IL- 25 and IL- 33, suggests an overall change in the lung immune environment induced by the NE immunization protocol.Conclusions and Clinical RelevanceThese results demonstrate that suppression of allergic airway inflammation and bronchial hyper- reactivity can be achieved using allergen- specific immunotherapy without significant reductions in allergen- specific IgE and suggest that ILC2 cells may be critical targets for this activity.The ability of intranasal vaccines to modulate allergic immune responses and inflammation in the lung was studied in two distinct models of allergic airway disease. Mice were sensitized to ovalbumin or cockroach allergen and subsequently received three immunizations with allergen in nanoemulsion adjuvant. Nanoemulsion vaccines modulated the allergen- specific cytokine milieu in the lungs to suppress Th2 cytokine production, alarmin expression and recruitment of ILC2s. The immune modulation in the lungs was associated with protection from allergen challenge- induced inflammation and reactivity.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/170274/1/cea13903.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/170274/2/cea13903_am.pd

NF-κB activation for RawBlue macrophages.

<p>Cells were treated for 24 h at 37°C with increasing concentrations of (A) NE, or (B) LPS. The level of activation was detected by SEAP activity as measured by absorbance at 650 nm normalized to the relative number of viable cells remaining after the 24 h treatment assessed by XTT (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126120#pone.0126120.s004" target="_blank">S4 Fig</a>). (Abbreviations CPC (C), Tween80 (W80), DODAC (D), P188 (P18), P407 (P4)).</p

Mouse and human iNKT cell agonist β-mannosylceramide reveals a distinct mechanism of tumor immunity

Type 1 or invariant NKT (iNKT) cell agonists, epitomized by α-galactosylceramide, protect against cancer largely by IFN-γ–dependent mechanisms. Here we describe what we believe to be a novel IFN-γ–independent mechanism induced by β-mannosylceramide, which also defines a potentially new class of iNKT cell agonist, with an unusual β-linked sugar. Like α-galactosylceramide, β-mannosylceramide directly activates iNKT cells from both mice and humans. In contrast to α-galactosylceramide, protection by β-mannosylceramide was completely dependent on NOS and TNF-α, neither of which was required to achieve protection with α-galactosylceramide. Moreover, at doses too low for either alone to protect, β-mannosylceramide synergized with α-galactosylceramide to protect mice against tumors. These results suggest that treatment with β-mannosylceramide provides a distinct mechanism of tumor protection that may allow efficacy where other agonists have failed. Furthermore, the ability of β-mannosylceramide to synergize with α-galactosylceramide suggests treatment with this class of iNKT agonist may provide protection against tumors in humans

Mucoadhesion of NE.

<p>(A) Particle size (Zave d) and (B) ZP of 0.1% NE incubated with and without 0.05 mg/mL mucin.</p