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Tytuł pozycji:

Low-dose 2-deoxy glucose stabilises tolerogenic dendritic cells and generates potent in vivo immunosuppressive effects.

Tytuł:
Low-dose 2-deoxy glucose stabilises tolerogenic dendritic cells and generates potent in vivo immunosuppressive effects.
Autorzy:
Christofi M; Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, Foresterhill, University of Aberdeen, Aberdeen, AB25 2ZD, Scotland, UK.
Le Sommer S; Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, Foresterhill, University of Aberdeen, Aberdeen, AB25 2ZD, Scotland, UK.
Mölzer C; Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, Foresterhill, University of Aberdeen, Aberdeen, AB25 2ZD, Scotland, UK. .
Klaska IP; Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, Foresterhill, University of Aberdeen, Aberdeen, AB25 2ZD, Scotland, UK.
Kuffova L; Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, Foresterhill, University of Aberdeen, Aberdeen, AB25 2ZD, Scotland, UK.; Eye Clinic, Aberdeen Royal Infirmary, Aberdeen, Scotland, UK.
Forrester JV; Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, Foresterhill, University of Aberdeen, Aberdeen, AB25 2ZD, Scotland, UK. .; Ocular Immunology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, WA, Australia. .; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA, Australia. .
Źródło:
Cellular and molecular life sciences : CMLS [Cell Mol Life Sci] 2021 Mar; Vol. 78 (6), pp. 2857-2876. Date of Electronic Publication: 2020 Oct 19.
Typ publikacji:
Journal Article
Język:
English
Imprint Name(s):
Publication: Basel : Springer
Original Publication: Basel ; Boston : Birkhauser, c1997-
MeSH Terms:
Dendritic Cells/*metabolism
Deoxyglucose/*pharmacology
Glycolysis/*drug effects
Immunosuppressive Agents/*pharmacology
Animals ; Antigens, Bacterial/immunology ; Autoimmune Diseases/drug therapy ; B7-2 Antigen/metabolism ; Bone Marrow Cells/cytology ; CD4-Positive T-Lymphocytes/cytology ; CD4-Positive T-Lymphocytes/metabolism ; Cell Proliferation/drug effects ; Dendritic Cells/cytology ; Dendritic Cells/drug effects ; Deoxyglucose/therapeutic use ; Histocompatibility Antigens Class II/metabolism ; Immunosuppressive Agents/therapeutic use ; Interleukin-10/metabolism ; Lactic Acid/metabolism ; Mice ; Mice, Inbred C57BL ; Oxidative Phosphorylation/drug effects ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction/drug effects
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Grant Information:
RG14251, RG12663 University of Aberdeen Development Trust
Contributed Indexing:
Keywords: Autoimmunity; Cell therapy; Metabolic programming; Tolerance; Zbtb46
Substance Nomenclature:
0 (Antigens, Bacterial)
0 (B7-2 Antigen)
0 (Histocompatibility Antigens Class II)
0 (Immunosuppressive Agents)
130068-27-8 (Interleukin-10)
33X04XA5AT (Lactic Acid)
9G2MP84A8W (Deoxyglucose)
EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
Entry Date(s):
Date Created: 20201019 Date Completed: 20210407 Latest Revision: 20210417
Update Code:
20240105
PubMed Central ID:
PMC8004500
DOI:
10.1007/s00018-020-03672-y
PMID:
33074350
Czasopismo naukowe
Cell therapies for autoimmune diseases using tolerogenic dendritic cells (tolDC) have been promisingly explored. A major stumbling block has been generating stable tolDC, with low risk of converting to mature immunogenic DC (mDC), exacerbating disease. mDC induction involves a metabolic shift to lactate production from oxidative phosphorylation (OXPHOS) and β-oxidation, the homeostatic energy source for resting DC. Inhibition of glycolysis through the administration of 2-deoxy glucose (2-DG) has been shown to prevent autoimmune disease experimentally but is not clinically feasible. We show here that treatment of mouse bone marrow-derived tolDC ex vivo with low-dose 2-DG (2.5 mM) (2-DGtolDC) induces a stable tolerogenic phenotype demonstrated by their failure to engage lactate production when challenged with mycobacterial antigen (Mtb). ~ 15% of 2-DGtolDC express low levels of MHC class II and 30% express CD86, while they are negative for CD40. 2-DGtolDC also express increased immune checkpoint molecules PDL-1 and SIRP-1α. Antigen-specific T cell proliferation is reduced in response to 2-DGtolDC in vitro. Mtb-stimulated 2-DGtolDC do not engage aerobic glycolysis but respond to challenge via increased OXPHOS. They also have decreased levels of p65 phosphorylation, with increased phosphorylation of the non-canonical p100 pathway. A stable tolDC phenotype is associated with sustained SIRP-1α phosphorylation and p85-AKT and PI3K signalling inhibition. Further, 2-DGtolDC preferentially secrete IL-10 rather than IL-12 upon Mtb-stimulation. Importantly, a single subcutaneous administration of 2-DGtolDC prevented experimental autoimmune uveoretinitis (EAU) in vivo. Inhibiting glycolysis of autologous tolDC prior to transfer may be a useful approach to providing stable tolDC therapy for autoimmune/immune-mediated diseases.

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