title: In human alloreactive CD4⁺ T-cells, dichloroacetate inhibits aerobic glycolysis, induces apoptosis and favors differentiation towards the regulatory T-cell subset instead of effector T-cell subsets.
abstract: Although kidney transplantation is the best therapy for end-stage renal disease, rejection remains a concern, and currently available immunosuppressive agents contribute to morbidity and mortality. Thus, novel immunosuppressive drugs are required. Dichloroacetate (DCA) is already used in the treatment of congenital lactic acidosis and characterized by limited toxicity. As DCA inhibits aerobic glycolysis, which is a prerequisite for CD4+ T-cell proliferation and differentiation into effector T-cells, its possible immunosuppressive role in mixed lymphocyte reaction (MLR), a model of alloreactivity, was investigated. Glucose and lactate concentrations were measured in the supernatants, and cell proliferation was assessed immunoenzymatically. CD4+ T‑cells were then isolated from the MLRs and the expression of cleaved caspase‑3, various enzymes involved in glycolysis, and the signature transcription factors of CD4+ T‑cell subsets were evaluated by western blotting. In MLRs, DCA decreased glucose consumption and aerobic glycolysis, while it exerted a negligible effect on cell proliferation. In CD4+ T‑cells, DCA induced apoptosis, and decreased the expression of glucose trasporter‑1, hexokinase II, lactate dehydrogenase‑A and phosphorylated pyruvate dehydrogenase, while it increased total pyruvate dehydrogenase. In addition, DCA increased the expression of transcription factor forkhead box P3, whereas it decreased the expression of T‑box transcription factor TBX21, trans‑acting T-cell-specific transcription factor GATA‑3 and retinoic acid receptor related orphan receptor‑γt. In conclusion, in alloreactive CD4+ T‑cells, DCA inhibits aerobic glycolysis, induces apoptosis and favors differentiation towards the regulatory T‑cell subset. These characteristics render it a promising immunosuppressive agent in the field of transplantation.
authors.affiliation: Department of Nephrology, Medical School, University of Thessaly, 41110 Larissa, Greece.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Eleftheriadis
authors.affiliation: Department of Nephrology, Medical School, University of Thessaly, 41110 Larissa, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Sounidaki
authors.affiliation: Department of Nephrology, Medical School, University of Thessaly, 41110 Larissa, Greece.
authors.forename: Georgios
authors.initials: G
authors.lastname: Pissas
authors.affiliation: Department of Nephrology, Medical School, University of Thessaly, 41110 Larissa, Greece.
authors.forename: Georgia
authors.initials: G
authors.lastname: Antoniadi
authors.affiliation: Department of Nephrology, Medical School, University of Thessaly, 41110 Larissa, Greece.
authors.forename: Vassilios
authors.initials: V
authors.lastname: Liakopoulos
authors.affiliation: Department of Nephrology, Medical School, University of Thessaly, 41110 Larissa, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Stefanidis
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D005260:Female; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D006593:Hexokinase / Q000378:metabolism; D006801:Humans; D045022:Lactate Dehydrogenases / Q000378:metabolism; D008297:Male; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D051272:Glucose Transporter Type 1; D014157:Transcription Factors; D003999:Dichloroacetic Acid; D045022:Lactate Dehydrogenases; D006593:Hexokinase; D053148:Caspase 3