title: Tolerogenic Dendritic Cells from Poorly Compensated Type 1 Diabetes Patients Have Decreased Ability To Induce Stable Antigen-Specific T Cell Hyporesponsiveness and Generation of Suppressive Regulatory T Cells.
abstract: Tolerogenic dendritic cells (tolDCs) may offer an interesting intervention strategy to re-establish Ag-specific tolerance in autoimmune diseases, including type 1 diabetes (T1D). T1D results from selective destruction of insulin-producing β cells leading to hyperglycemia that, in turn, specifically affects a patient's immune system. In this study, we prepared monocyte-derived tolDCs modulated by dexamethasone and vitamin D2from 31 T1D patients with optimal glycemic control and 60 T1D patients with suboptimal glycemic control and assessed their tolerogenic properties in correlation with metabolic state of patients. tolDCs differentiated from both groups of patients acquired a regulatory phenotype and an anti-inflammatory profile. Interestingly, tolDCs from well-controlled patients expressed higher levels of inhibitory molecules IL-T3 and PD-L1. Additionally, glutamic acid decarboxylase (GAD)65-loaded tolDCs from well-controlled patients decreased significantly primary Th1/Th17 responses, induced stable GAD65-specific T cell hyporesponsiveness, and suppressed markedly control DC-induced GAD65-specific T cell activation compared with poorly controlled patients. The ability of tolDCs from poorly controlled patients to induce durable GAD65-specific T cell hyporesponsiveness was reversed once the control of glycemia improved. In both groups of patients, tolDCs were able to induce regulatory T cells from autologous naive CD4+T cells. However, regulatory T cells from well-controlled patients had better suppressive abilities. The functionality of tolDCs was confirmed in the adoptive transfer model of NOD-SCID mice where tolDCs delayed diabetes onset. These results suggest that metabolic control of T1D affects the functional characteristics of tolDCs and subsequent effector T cell responses. Metabolic control may be relevant for refining inclusion criteria of clinical trials in the settings of T1D.
authors.affiliation: Sotio a.s., 170 00 Prague, Czech Republic.|Department of Immunology, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic.
authors.forename: Klára
authors.initials: K
authors.lastname: Dáňová
authors.affiliation: Sotio a.s., 170 00 Prague, Czech Republic.|Department of Immunology, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic.
authors.forename: Anna
authors.initials: A
authors.lastname: Grohová
authors.affiliation: Sotio a.s., 170 00 Prague, Czech Republic.
authors.forename: Pavla
authors.initials: P
authors.lastname: Strnadová
authors.affiliation: Department of Immunology and Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, v.v.i., 142 20 Prague, Czech Republic.
authors.forename: David P
authors.initials: DP
authors.lastname: Funda
authors.affiliation: Department of Pediatrics, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic; and.
authors.forename: Zdeněk
authors.initials: Z
authors.lastname: Šumník
authors.affiliation: Department of Pediatrics, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic; and.
authors.forename: Jan
authors.initials: J
authors.lastname: Lebl
authors.affiliation: Department of Pediatrics, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic; and.
authors.forename: Ondřej
authors.identifier: 0000-0002-0526-8714
authors.initials: O
authors.lastname: Cinek
authors.affiliation: Department of Pediatrics, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic; and.
authors.forename: Štěpánka
authors.initials: Š
authors.lastname: Průhová
authors.affiliation: Department of Pediatrics, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic; and.
authors.forename: Stanislava
authors.initials: S
authors.lastname: Koloušková
authors.affiliation: Department of Pediatrics, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic; and.
authors.forename: Barbora
authors.initials: B
authors.lastname: Obermannová
authors.affiliation: Department of Pediatrics, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic; and.
authors.forename: Lenka
authors.initials: L
authors.lastname: Petruželková
authors.affiliation: Department of Immunology, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic.
authors.forename: Anna
authors.initials: A
authors.lastname: Šedivá
authors.affiliation: Department of Immunology and Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, v.v.i., 142 20 Prague, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Fundová
authors.affiliation: The Bartholin Institute, Rigshospitalet, 2100 Copenhagen, Denmark.
authors.forename: Karsten
authors.initials: K
authors.lastname: Buschard
authors.affiliation: Sotio a.s., 170 00 Prague, Czech Republic.|Department of Immunology, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic.
authors.forename: Radek
authors.initials: R
authors.lastname: Špíšek
authors.affiliation: Sotio a.s., 170 00 Prague, Czech Republic; palova@sotio.com.|Department of Immunology, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic.
authors.forename: Lenka
authors.identifier: 0000-0002-3992-2534
authors.initials: L
authors.lastname: Palová-Jelínková
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D003713:Dendritic Cells / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*