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1.
Int J Pharm ; 660: 124254, 2024 Jul 20.
Article in English | MEDLINE | ID: mdl-38795934

ABSTRACT

Cancer vaccines can be utilized in combination with checkpoint inhibitors to optimally stimulate the anti-tumor immune response. Uptake of vaccine antigen by antigen presenting cells (APCs) is a prerequisite for T cell priming, but often relies on non-specific mechanisms. Here, we have developed a novel vaccination strategy consisting of cancer antigen-containing liposomes conjugated with CD169- or DC-SIGN-specific nanobodies (single domain antibodies) to achieve specific uptake by APCs. Our studies demonstrate efficient nanobody liposome uptake by human and murine CD169+ and DC-SIGN+ APCs in vitro and in vivo when compared to control liposomes or liposomes with natural ligands for CD169 and DC-SIGN. Uptake of CD169 nanobody liposomes resulted in increased T cell activation by human APCs and stimulated naive T cell priming in mouse models. In conclusion, while nanobody liposomes have previously been utilized to direct drugs to tumors, here we show that nanobody liposomes can be applied as vaccination strategy that can be extended to other receptors on APCs in order to elicit a potent immune response against tumor antigens.


Subject(s)
Antigen-Presenting Cells , Cancer Vaccines , Liposomes , Mice, Inbred C57BL , Single-Domain Antibodies , T-Lymphocytes , Animals , Cancer Vaccines/administration & dosage , Cancer Vaccines/immunology , Single-Domain Antibodies/immunology , Single-Domain Antibodies/administration & dosage , Humans , T-Lymphocytes/immunology , Mice , Antigen-Presenting Cells/immunology , Female , Antigens, Neoplasm/immunology , Antigens, Neoplasm/administration & dosage , Lymphocyte Activation/drug effects
2.
J Exp Med ; 211(7): 1465-83, 2014 Jun 30.
Article in English | MEDLINE | ID: mdl-24935259

ABSTRACT

Myelin oligodendrocyte glycoprotein (MOG), a constituent of central nervous system myelin, is an important autoantigen in the neuroinflammatory disease multiple sclerosis (MS). However, its function remains unknown. Here, we show that, in healthy human myelin, MOG is decorated with fucosylated N-glycans that support recognition by the C-type lectin receptor (CLR) DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) on microglia and DCs. The interaction of MOG with DC-SIGN in the context of simultaneous TLR4 activation resulted in enhanced IL-10 secretion and decreased T cell proliferation in a DC-SIGN-, glycosylation-, and Raf1-dependent manner. Exposure of oligodendrocytes to proinflammatory factors resulted in the down-regulation of fucosyltransferase expression, reflected by altered glycosylation at the MS lesion site. Indeed, removal of fucose on myelin reduced DC-SIGN-dependent homeostatic control, and resulted in inflammasome activation, increased T cell proliferation, and differentiation toward a Th17-prone phenotype. These data demonstrate a new role for myelin glycosylation in the control of immune homeostasis in the healthy human brain through the MOG-DC-SIGN homeostatic regulatory axis, which is comprised by inflammatory insults that affect glycosylation. This phenomenon should be considered as a basis to restore immune tolerance in MS.


Subject(s)
Brain/immunology , Cell Adhesion Molecules/immunology , Immune Tolerance/physiology , Inflammasomes/immunology , Lectins, C-Type/immunology , Myelin-Oligodendrocyte Glycoprotein/immunology , Receptors, Cell Surface/immunology , Th17 Cells/immunology , Animals , Brain/cytology , CHO Cells , Cell Adhesion Molecules/genetics , Cell Proliferation , Cricetinae , Cricetulus , Female , Humans , Inflammasomes/genetics , Inflammation Mediators/immunology , Interleukin-10/genetics , Interleukin-10/immunology , Lectins, C-Type/genetics , Male , Myelin-Oligodendrocyte Glycoprotein/genetics , Proto-Oncogene Proteins c-raf/genetics , Proto-Oncogene Proteins c-raf/immunology , Receptors, Cell Surface/genetics , Th17 Cells/cytology , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/immunology
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