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J Immunol. 2015 Sep 1;195(5):2216-23. doi: 10.4049/jimmunol.1402989. Epub 2015 Jul 31.

Cholesterol Modification of p40-Specific Small Interfering RNA Enables Therapeutic Targeting of Dendritic Cells.

Author information

1
Department of Dermatology, Eberhard Karls University of Tübingen, D-72076 Tübingen, Germany; and.
2
Department of Oncology, University Hospital Zurich, CH-8044 Zurich, Switzerland.
3
Department of Dermatology, Eberhard Karls University of Tübingen, D-72076 Tübingen, Germany; and kamran.ghoreschi@med.uni-tuebingen.de mrocken@med.uni-tuebingen.de.

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.

PMID:
26232431
DOI:
10.4049/jimmunol.1402989
[Indexed for MEDLINE]
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