TY - JOUR

T1 - The adjuvant mechanism of cationic dimethyldioctadecylammonium liposomes

AU - Korsholm, Karen Smith

AU - Agger, Else Marie

AU - Foged, Camilla

AU - Christensen, Dennis

AU - Dietrich, Jes

AU - Andersen, Claire Swetman

AU - Geisler, Carsten

AU - Andersen, Peter

N1 - Keywords: Adjuvants, Immunologic; Adsorption; Animals; Antigen Presentation; Antigens; Cell Differentiation; Cells, Cultured; Dendritic Cells; Female; Liposomes; Mice; Mice, Inbred BALB C; Mice, Transgenic; Ovalbumin; Quaternary Ammonium Compounds

PY - 2007

Y1 - 2007

N2 - Cationic liposomes are being used increasingly as efficient adjuvants for subunit vaccines but their precise mechanism of action is still unknown. Here, we investigated the adjuvant mechanism of cationic liposomes based on the synthetic amphiphile dimethyldioctadecylammonium (DDA). The liposomes did not have an effect on the maturation of murine bone-marrow-derived dendritic cells (BM-DCs) related to the surface expression of major histocompatibility complex (MHC) class II, CD40, CD80 and CD86. We found that ovalbumin (OVA) readily associated with the liposomes (> 90%) when mixed in equal concentrations. This efficient adsorption onto the liposomes led to an enhanced uptake of OVA by BM-DCs as assessed by flow cytometry and confocal fluorescence laser-scanning microscopy. This was an active process, which was arrested at 4 degrees and by an inhibitor of actin-dependent endocytosis, cytochalasin D. In vivo studies confirmed the observed effect because adsorption of OVA onto DDA liposomes enhanced the uptake of the antigen by peritoneal exudate cells after intraperitoneal injection. The liposomes targeted antigen preferentially to antigen-presenting cells because we only observed a minimal uptake by T cells in mixed splenocyte cultures. The adsorption of antigen onto the liposomes increased the efficiency of antigen presentation more than 100 times in a responder assay with MHC class II-restricted OVA-specific T-cell receptor transgenic DO11.10 T cells. Our data therefore suggest that the primary adjuvant mechanism of cationic DDA liposomes is to target the cell membrane of antigen-presenting cells, which subsequently leads to enhanced uptake and presentation of antigen.

AB - Cationic liposomes are being used increasingly as efficient adjuvants for subunit vaccines but their precise mechanism of action is still unknown. Here, we investigated the adjuvant mechanism of cationic liposomes based on the synthetic amphiphile dimethyldioctadecylammonium (DDA). The liposomes did not have an effect on the maturation of murine bone-marrow-derived dendritic cells (BM-DCs) related to the surface expression of major histocompatibility complex (MHC) class II, CD40, CD80 and CD86. We found that ovalbumin (OVA) readily associated with the liposomes (> 90%) when mixed in equal concentrations. This efficient adsorption onto the liposomes led to an enhanced uptake of OVA by BM-DCs as assessed by flow cytometry and confocal fluorescence laser-scanning microscopy. This was an active process, which was arrested at 4 degrees and by an inhibitor of actin-dependent endocytosis, cytochalasin D. In vivo studies confirmed the observed effect because adsorption of OVA onto DDA liposomes enhanced the uptake of the antigen by peritoneal exudate cells after intraperitoneal injection. The liposomes targeted antigen preferentially to antigen-presenting cells because we only observed a minimal uptake by T cells in mixed splenocyte cultures. The adsorption of antigen onto the liposomes increased the efficiency of antigen presentation more than 100 times in a responder assay with MHC class II-restricted OVA-specific T-cell receptor transgenic DO11.10 T cells. Our data therefore suggest that the primary adjuvant mechanism of cationic DDA liposomes is to target the cell membrane of antigen-presenting cells, which subsequently leads to enhanced uptake and presentation of antigen.

U2 - 10.1111/j.1365-2567.2007.02560.x

DO - 10.1111/j.1365-2567.2007.02560.x

M3 - Journal article

C2 - 17302734

VL - 121

SP - 216

EP - 226

JO - Immunology

JF - Immunology

SN - 0019-2805

IS - 2

ER -