title: Effect of incorporating cholesterol into DDA:TDB liposomal adjuvants on bilayer properties, biodistribution, and immune responses.
abstract: Cholesterol is an abundant component of mammalian cell membranes and has been extensively studied as an artificial membrane stabilizer in a wide range of phospholipid liposome systems. In this study, the aim was to investigate the role of cholesterol in cationic liposomal adjuvant system based on dimethyldioctadecylammonium (DDA) and trehalose 6,6'-dibehenate (TDB) which has been shown as a strong adjuvant system for vaccines against a wide range of diseases. Packaging of cholesterol within DDA:TDB liposomes was investigated using differential scanning calorimetery and surface pressure-area isotherms of lipid monolayers; incorporation of cholesterol into liposomal membranes promoted the formation of a liquid-condensed monolayer and removed the main phase transition temperature of the system, resulting in an increased bilayer fluidity and reduced antigen retention in vitro. In vivo biodistribution studies found that this increase in membrane fluidity did not alter deposition of liposomes and antigen at the site of injection. In terms of immune responses, early (12 days after immunization) IgG responses were reduced by inclusion of cholesterol; thereafter there were no differences in antibody (IgG, IgG1, IgG2b) responses promoted by DDA:TDB liposomes with and without cholesterol. However, significantly higher levels of IFN-gamma were induced by DDA:TDB liposomes, and liposome uptake by macrophages in vitro was also shown to be higher for DDA:TDB liposomes compared to their cholesterol-containing counterparts, suggesting that small changes in bilayer mechanics can impact both cellular interactions and immune responses.
authors.affiliation: Medicines Research Unit, School of Life and Health Sciences, Aston University , Birmingham, B4 7ET United Kingdom.
authors.forename: Randip
authors.initials: R
authors.lastname: Kaur
authors.forename: Malou
authors.initials: M
authors.lastname: Henriksen-Lacey
authors.forename: Jitinder
authors.initials: J
authors.lastname: Wilkhu
authors.forename: Andrew
authors.initials: A
authors.lastname: Devitt
authors.forename: Dennis
authors.initials: D
authors.lastname: Christensen
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Perrie
mesh_terms: D000276:Adjuvants, Immunologic / Q000737:chemistry*; D000818:Animals; D002152:Calorimetry, Differential Scanning; D002784:Cholesterol / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics*; D005260:Female; D006017:Glycolipids / Q000737:chemistry*; D006801:Humans; D007114:Immunization; D007074:Immunoglobulin G / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008560:Membrane Fluidity / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D044367:Phase Transition; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000737:chemistry*; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D000276:Adjuvants, Immunologic; D006017:Glycolipids; D007074:Immunoglobulin G; D008051:Lipid Bilayers; D008081:Liposomes; D010743:Phospholipids; D000644:Quaternary Ammonium Compounds; C507803:trehalose 6,6'-dibehenate; C015831:dimethyldioctadecylammonium; D007371:Interferon-gamma; D002784:Cholesterol