title: Cholesterol Modification of p40-Specific Small Interfering RNA Enables Therapeutic Targeting of Dendritic Cells.
abstract: Small interfering RNA (siRNA)-based therapies allow targeted correction of molecular defects in distinct cell populations. Although efficient in multiple cell populations, dendritic cells (DCs) seem to resist siRNA delivery. Using fluorescence labeling and radiolabeling, we show that cholesterol modification enables siRNA uptake by DCs in vitro and in vivo. Delivery of cholesterol-modified p40 siRNA selectively abolished p40 transcription and suppressed TLR-triggered p40 production by DCs. During immunization with peptide in CFA, cholesterol-modified p40 siRNA generated p40-deficient, IL-10-producing DCs that prevented IL-17/Th17 and IFN-γ/Th1 responses. Only cholesterol-modified p40-siRNA established protective immunity against experimental autoimmune encephalomyelitis and suppressed IFN-γ and IL-17 expression by CNS-infiltrating mononuclear cells without inducing regulatory T cells. Because cholesterol-modified siRNA can thus modify selected DC functions in vivo, it is intriguing for targeted immune therapy of allergic, autoimmune, or neoplastic diseases.
authors.affiliation: Department of Dermatology, Eberhard Karls University of Tübingen, D-72076 Tübingen, Germany; and.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brück
authors.affiliation: Department of Oncology, University Hospital Zurich, CH-8044 Zurich, Switzerland.
authors.forename: Steve
authors.initials: S
authors.lastname: Pascolo
authors.affiliation: Department of Dermatology, Eberhard Karls University of Tübingen, D-72076 Tübingen, Germany; and.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Fuchs
authors.affiliation: Department of Dermatology, Eberhard Karls University of Tübingen, D-72076 Tübingen, Germany; and.
authors.forename: Christina
authors.initials: C
authors.lastname: Kellerer
authors.affiliation: Department of Dermatology, Eberhard Karls University of Tübingen, D-72076 Tübingen, Germany; and.
authors.forename: Ivana
authors.initials: I
authors.lastname: Glocova
authors.affiliation: Department of Dermatology, Eberhard Karls University of Tübingen, D-72076 Tübingen, Germany; and.
authors.forename: Julia
authors.initials: J
authors.lastname: Geisel
authors.affiliation: Department of Dermatology, Eberhard Karls University of Tübingen, D-72076 Tübingen, Germany; and.
authors.forename: Katja
authors.initials: K
authors.lastname: Dengler
authors.affiliation: Department of Dermatology, Eberhard Karls University of Tübingen, D-72076 Tübingen, Germany; and.
authors.forename: Amir S
authors.initials: AS
authors.lastname: Yazdi
authors.affiliation: Department of Dermatology, Eberhard Karls University of Tübingen, D-72076 Tübingen, Germany; and kamran.ghoreschi@med.uni-tuebingen.de mrocken@med.uni-tuebingen.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Röcken
authors.affiliation: Department of Dermatology, Eberhard Karls University of Tübingen, D-72076 Tübingen, Germany; and kamran.ghoreschi@med.uni-tuebingen.de mrocken@med.uni-tuebingen.de.
authors.forename: Kamran
authors.initials: K
authors.lastname: Ghoreschi
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000737:chemistry / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D007114:Immunization / Q000379:methods; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D053762:Interleukin-12 Subunit p40 / Q000097:blood / Q000235:genetics / Q000276:immunology*; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D034741:RNA, Small Interfering / Q000235:genetics / Q000276:immunology*; D000067492:RNAi Therapeutics / Q000379:methods; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D053762:Interleukin-12 Subunit p40; D034741:RNA, Small Interfering; D016753:Interleukin-10; D002784:Cholesterol