IL-33 Is Essential for Adjuvant Effect of Hydroxypropyl-β-Cyclodexrin on the Protective Intranasal Influenza Vaccination

Abstract

Vaccine adjuvants are traditionally used to augment and modulate the immunogenicity of vaccines, although in many cases it is unclear which specific molecules contribute to their stimulatory activity. We previously reported that both subcutaneous and intranasal administration of hydroxypropyl-β-cyclodextrin (HP-β-CD), a pharmaceutical excipient widely used to improve solubility, can act as an effective adjuvant for an influenza vaccine. However, the mechanisms by which mucosal immune pathway is critical for the intranasal adjuvant activity of HP-β-CD have not been fully delineated. Here, we show that intranasally administered HP-β-CD elicits a temporary release of IL-33 from alveolar epithelial type 2 cells in the lung; notably, IL-33 expression in these cells is not stimulated following the use of other vaccine adjuvants. The experiments using gene deficient mice suggested that IL-33/ST2 signaling is solely responsible for the adjuvant effect of HP-β-CD when it is administered intranasally. In contrast, the subcutaneous injection of HP-β-CD and the intranasal administration of alum, as a damage-associated molecular patterns (DAMPs)-inducing adjuvant, or cholera toxin, as a mucosal adjuvant, enhanced humoral immunity in an IL-33-independent manner, suggesting that the IL-33/ST2 pathway is unique to the adjuvanticity of intranasally administered HP-β-CD. Furthermore, the release of IL-33 was involved in the protective immunity against influenza virus infection which is induced by the intranasal administration of HP-β-CD-adjuvanted influenza split vaccine. In conclusion, our results suggest that an understanding of administration route-and tissue-specific immune responses is crucial for the design of unique vaccine adjuvants.

Versatile Nasal Application of Cyclodextrins: Excipients and/or Actives?

“…After intranasal administration, the influenza vaccine containing HP-β-CD induced the secretion of specific IgA and IgG antibodies both in the nasal mucosa and in the blood, providing higher and complete protection against infection than the vaccine without HP-β-CD [ 93 ]. The mechanism action of HP-β-CD resulted in the induction of the temporary release of IL-33 cytokines from alveolar epithelial cells in the lung; this effect was not observed after subcutaneous injection either after intranasal administration of other vaccine adjuvants [ 94 ]. Furthermore, HP-β-CD is safer than aluminum salt because it induces a low production of IgE antibodies [ 93 ].…”

Immunogenicity and Toxicity of Different Adjuvants Can Be Characterized by Profiling Lung Biomarker Genes After Nasal Immunization

“…Alum and AddaVax elicit weak cytotoxicity, which involves the release of DAMPs from injured cells (or tissues) ( 58 – 60 ). The release of DAMPs, such as dsDNA ( 58 ), IL-33 ( 72 ), high mobility group box-1 (HMGB-1) ( 73 ), and IL-1α ( 74 ), has been reported to be associated with adjuvant efficacy. Among these, IL-33 ( 72 , 74 ) and IL-1α ( 74 ) are reported to serve as critical mediators of IgA expression in response to nasal vaccination.…”

“…The release of DAMPs, such as dsDNA ( 58 ), IL-33 ( 72 ), high mobility group box-1 (HMGB-1) ( 73 ), and IL-1α ( 74 ), has been reported to be associated with adjuvant efficacy. Among these, IL-33 ( 72 , 74 ) and IL-1α ( 74 ) are reported to serve as critical mediators of IgA expression in response to nasal vaccination. To evaluate the cytotoxicity of the tested adjuvants, the concentration of dsDNA [the host DNA, an indicator of cell death ( 45 )] in BALF specimens was measured 16 h after nasal vaccination ( Figure 5A ).…”

“…In lungs, the BALF dsDNA concentrations and the IL-1α levels tended to correlate, which suggests that Timp1 acts as a marker for cytotoxicity in lungs and is associated with the release of DAMPs (Figures 5A,B). DAMPs are important for exerting adjuvant efficacy as they accelerate innate immunity by enhancing mucosal IgA expression (72,74). The Timp1 expression levels were found to have excellent potential as predictors of BALF IgA production in nasal influenza vaccine ( Figure 5C).…”

Rational Design of Thermosensitive Hydrogel to Deliver Nanocrystals with Intranasal Administration for Brain Targeting in Parkinson’s Disease

“…In addition, by evading first-pass hepatic metabolism, this approach also reduces the rates of drug degradation. Several nanoparticle-based strategies, such as solid lipid nanoparticles [ 15 , 16 ], nanoemulsions [ 17 ], liposomes [ 18 ], polymeric micelles [ 19 , 20 ], and cyclodextrin derived [ 21 ] have been used to achieve efficient intranasal drug delivery to date. Nanocrystal- (NC-) based delivery platforms are particularly promising in this therapeutic context, as they consist of small crystals (<500 nm) stabilized with surfactants or polymeric steric stabilizers [ 22 , 23 ].…”