Abstract
2-Hydroxypropyl-β-cyclodextrin (HP-β-CD) is a chemically modified cyclic oligosaccharide produced from starch that is commonly used as an excipient. Although HP-β-CD has been suggested as a potential adjuvant for vaccines, its immunological properties and mechanism of action have yet to be characterized. In the present study, we investigated the maturation and activation of human dendritic cells (DCs) treated with HP-β-CD. We found that DCs stimulated with HP-β-CD exhibited a remarkable upregulation of costimulatory molecules, MHC proteins, and PD-L1/L2. In addition, the production of cytokines, such as TNF-α, IL-6, and IL-10, was modestly increased in DCs when treated with HP-β-CD. Furthermore, HP-β-CD-sensitized DCs markedly induced the proliferation and activation of autologous T lymphocytes. HP-β-CD also induced a lipid raft formation in DCs. In contrast, filipin, a lipid raft inhibitor, attenuated HP-β-CD-induced DC maturation, the cytokine expression, and the T lymphocyte-stimulating activities. To determine the in vivo relevance of the results, we investigated the adjuvanticity of HP-β-CD and the modulation of DCs in a mouse footpad immunization model. When mice were immunized with ovalbumin in the presence of HP-β-CD through a hind footpad, serum ovalbumin-specific antibodies were markedly elevated. Concomitantly, DC populations expressing CD11c and MHC class II were increased in the draining lymph nodes, and the expression of costimulatory molecules was upregulated. Collectively, our data suggest that HP-β-CD induces phenotypic and functional maturation of DCs mainly mediated through lipid raft formation, which might mediate the adjuvanticity of HP-β-CD.
Highlights
Cyclodextrins are cyclic oligosaccharides composed of sugar molecules
Recombinant murine granulocyte macrophage-colony stimulating factor (GM-CSF) was obtained from CreaGene. 3,3′,5,5′-Tetramethylbenzidine (TMB) substrate and enzymelinked immunosorbent assay (ELISA) kits for the quantification of human TNF-α, IL-6, IL-12p70, and IL-10, and mouse TNF-α and IL-6 were purchased from BioLegend (San Diego, CA, USA). 5,6-Carboxyfluorescein diacetate succinimidyl ester (CFDA-SE) and the Vybrant® Alexa Fluor® 594 lipid raft-labeling kit were obtained from Molecular Probes (Eugene, OR, USA)
These results suggest that HP-β-CD upregulates the expression of maturation markers coincident with weak induction of cytokines in human monocyte-derived dendritic cells (DCs)
Summary
Cyclodextrins are cyclic oligosaccharides composed of sugar molecules. These oligosaccharides consist of 6, 7, or 8 α-d-glucopyranose units bound via α-1,4-glycosidic linkages, namely, α-, β-, or γ-cyclodextrin, respectively. Cyclodextrins can efficiently form water-soluble inclusion complexes with hydrophobic molecules, which enhances the solubility and bioavailability of many insoluble compounds [2, 3]. DC Maturation by HP-β-CD effects of drugs by controlling compound release, increasing their stability, and regulating the metabolism of the incorporated molecules [4]. Due to these physicochemical properties, cyclodextrins are commonly utilized as excipients of pharmaceutical agents, food products, and cosmetics
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