title: Tolerogenic nanoparticles inhibit T cell-mediated autoimmunity through SOCS2.
abstract: Type 1 diabetes (T1D) is a T cell-dependent autoimmune disease that is characterized by the destruction of insulin-producing β cells in the pancreas. The administration to patients of ex vivo-differentiated FoxP3(+) regulatory T (Treg) cells or tolerogenic dendritic cells (DCs) that promote Treg cell differentiation is considered a potential therapy for T1D; however, cell-based therapies cannot be easily translated into clinical practice. We engineered nanoparticles (NPs) to deliver both a tolerogenic molecule, the aryl hydrocarbon receptor (AhR) ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), and the β cell antigen proinsulin (NPITE+Ins) to induce a tolerogenic phenotype in DCs and promote Treg cell generation in vivo. NPITE+Ins administration to 8-week-old nonobese diabetic mice suppressed autoimmune diabetes. NPITE+Ins induced a tolerogenic phenotype in DCs, which was characterized by a decreased ability to activate inflammatory effector T cells and was concomitant with the increased differentiation of FoxP3(+) Treg cells. The induction of a tolerogenic phenotype in DCs by NPs was mediated by the AhR-dependent induction of Socs2, which resulted in inhibition of nuclear factor κB activation and proinflammatory cytokine production (properties of tolerogenic DCs). Together, these data suggest that NPs constitute a potential tool to reestablish tolerance in T1D and potentially other autoimmune disorders.
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ada
authors.initials: A
authors.lastname: Yeste
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Maisa C
authors.initials: MC
authors.lastname: Takenaka
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ivan D
authors.initials: ID
authors.lastname: Mascanfroni
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Meghan
authors.initials: M
authors.lastname: Nadeau
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Kenison
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Bonny
authors.initials: B
authors.lastname: Patel
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ann-Marcia
authors.initials: AM
authors.lastname: Tukpah
authors.affiliation: Department of Medicine, Diabetes Division, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Jenny Aurielle B
authors.initials: JA
authors.lastname: Babon
authors.affiliation: Department of Medicine, Diabetes Division, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: DeNicola
authors.affiliation: Department of Medicine, Diabetes Division, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Sally C
authors.initials: SC
authors.lastname: Kent
authors.affiliation: CABIMER-Andalusian Center for Molecular Biology and Regenerative Medicine (Consejo Superior de Investigaciones Científicas-University of Seville-Universidad Pablo de Olavide), Seville 41092, Spain. Department of Medical Biochemistry, Molecular Biology and Immunology, University of Seville Medical School, Seville 41009, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Pozo
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA. fquintana@rics.bwh.harvard.edu.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Quintana
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000819:agonists / Q000235:genetics / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000473:pathology; D016688:Mice, Inbred NOD; D053758:Nanoparticles / Q000737:chemistry / Q000627:therapeutic use; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000235:genetics / Q000276:immunology; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D007211:Indoles; D018336:Receptors, Aryl Hydrocarbon; D050826:Suppressor of Cytokine Signaling Proteins; D013844:Thiazoles; C548651:2-(1'H-indole-3'-carbonyl)thiazole-4-carboxylic acid methyl ester; C111235:AHR protein, human; C484722:Ahr protein, mouse; C106643:SOCS2 protein, human; C491409:Socs2 protein, mouse