title: Nonviral delivery of small interfering RNA into pancreas-associated immune cells prevents autoimmune diabetes.
abstract: The development of small interfering RNA (siRNA) for the treatment of human disorders has been often hampered by their low transfection efficiency in vivo. In order to overcome this major drawback, various in vivo siRNA transfection methods have been developed. However, their capacity to transfect immune or insulin-producing β-cells within the pancreas for the treatment of autoimmune diabetes remains undetermined. We found that lipid- or polyethylenimine-based delivery agents were efficient to address siRNA molecules within pancreas-associated antigen-presenting cells (APCs) (but not β-cells) and particularly a CD11b(+) cell population comprising both CD11b(+)CD11c(neg) macrophages and CD11b(+)CD11c(+) dendritic cells. However, the route of administration and the carrier composition greatly affected the transfection efficacy. Therapeutically, we showed that early (starting at 6-week-old) short-course treatment with lipid/Alox15-specific siRNA complex promoted long-term protection from type 1 diabetes (T1D) in wild-type (WT) nonobese diabetic (NOD) mice. Alox15 downregulation in pancreas-associated CD11b(+) cells significantly upregulated a variety of costimulatory molecules and particularly the programmed death 1 ligand 1 (PD-L1) pathway involved in tolerance induction. Concomitantly, we found that regulatory T cells were increased in the pancreas of lipid/Alox15 siRNA-treated NOD mice. Collectively, our data provide new insights into the development of siRNA-based therapeutics for T1D.
authors.affiliation: Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Wilhem
authors.initials: W
authors.lastname: Leconet
authors.forename: Pierre
authors.initials: P
authors.lastname: Petit
authors.forename: Sylvie
authors.initials: S
authors.lastname: Peraldi-Roux
authors.forename: Damien
authors.initials: D
authors.lastname: Bresson
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D005260:Female; D005434:Flow Cytometry; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000737:chemistry; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D054367:Receptors, CXCR3 / Q000235:genetics / Q000378:metabolism
chemical_list: D054357:Chemokine CXCL10; C515188:Cxcr3 protein, mouse; D008081:Liposomes; D034741:RNA, Small Interfering; D054367:Receptors, CXCR3; D011092:Polyethylene Glycols; C521960:Alox15 protein, mouse; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase