CD4+ CD25+ regulatory T cells partially mediate the beneficial effects of FTY720, a sphingosine-1-phosphate analogue, during ischaemia/reperfusion-induced acute kidney injury

Myung-Gyu Kim, So Young Lee, Yoon Sook Ko, Hee Young Lee, Sang Kyung Jo, Won Yong Cho, Hyoung Kyu Kim

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Background. The synthetic sphingosine-1-phosphate (S1P) analogue, FTY720, attenuates ischaemia/reperfusion (I/R) injury by inducing peripheral lymphopaenia. Recent studies suggest that FTY720 may also exert protective effects by modulating dendritic cell (DC) function or directly affecting regulatory T cells (Tregs). The purpose of the present study was to examine whether the beneficial effect of FTY720 in I/R-induced acute kidney injury (AKI) involves modulation of DCs or Tregs.Methods. Mice underwent bilateral ischaemia, and FTY720 or vehicle was then administered. Biochemical values, histological kidney damage and tissue inflammation were assessed. Phenotype and function of DCs in blood/spleen or kidney were also examined by flow cytometry or mixed lymphocyte reaction (MLR) assay. Percent Tregs or FoxP3 mRNA expression was examined in kidney and spleen, and depletion and adoptive transfer of Tregs were also performed.Results. Treatment with FTY720 attenuated I/R kidney injury and reduced inflammation. The beneficial effect of FTY720 was associated with expansion of peripheral CD11b+ CD11c+ DC and with maturation of spleen CD11c+ DC, which showed impaired allostimulatory capacity. FTY720-treated animals also showed a higher frequency of CD4 + CD25+ Tregs and an upregulation of FoxP3 mRNA expression in spleen and kidney. In vitro experiments showed that FTY720 induced expansion of Tregs, possibly via conversion from non-Tregs to Tregs. Depletion and adoptive transfer of Tregs were associated with loss and recovery of the beneficial effects of FTY720.Conclusion. These results suggest that the beneficial effects of FTY720 in I/R injury may be partially mediated by DC modulation or by increasing Treg activity. Further studies that identify tolerance induction mechanisms will be useful for developing strategies for the prevention or treatment of AKI.

Original languageEnglish
Pages (from-to)111-124
Number of pages14
JournalNephrology Dialysis Transplantation
Volume26
Issue number1
DOIs
Publication statusPublished - 2011 Jan 1

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Regulatory T-Lymphocytes
Acute Kidney Injury
Reperfusion
Ischemia
Dendritic Cells
Kidney
Spleen
Reperfusion Injury
Adoptive Transfer
Fingolimod Hydrochloride
sphingosine 1-phosphate
Inflammation
Messenger RNA
Mixed Lymphocyte Culture Test
Lymphopenia
Flow Cytometry
Up-Regulation
Phenotype

Keywords

  • acute kidney injury
  • dendritic cell
  • FTY720
  • regulatory T lymphocyte

ASJC Scopus subject areas

  • Nephrology
  • Transplantation

Cite this

@article{35f43aa98cae48fd84d0cb06b733a356,
title = "CD4+ CD25+ regulatory T cells partially mediate the beneficial effects of FTY720, a sphingosine-1-phosphate analogue, during ischaemia/reperfusion-induced acute kidney injury",
abstract = "Background. The synthetic sphingosine-1-phosphate (S1P) analogue, FTY720, attenuates ischaemia/reperfusion (I/R) injury by inducing peripheral lymphopaenia. Recent studies suggest that FTY720 may also exert protective effects by modulating dendritic cell (DC) function or directly affecting regulatory T cells (Tregs). The purpose of the present study was to examine whether the beneficial effect of FTY720 in I/R-induced acute kidney injury (AKI) involves modulation of DCs or Tregs.Methods. Mice underwent bilateral ischaemia, and FTY720 or vehicle was then administered. Biochemical values, histological kidney damage and tissue inflammation were assessed. Phenotype and function of DCs in blood/spleen or kidney were also examined by flow cytometry or mixed lymphocyte reaction (MLR) assay. Percent Tregs or FoxP3 mRNA expression was examined in kidney and spleen, and depletion and adoptive transfer of Tregs were also performed.Results. Treatment with FTY720 attenuated I/R kidney injury and reduced inflammation. The beneficial effect of FTY720 was associated with expansion of peripheral CD11b+ CD11c+ DC and with maturation of spleen CD11c+ DC, which showed impaired allostimulatory capacity. FTY720-treated animals also showed a higher frequency of CD4 + CD25+ Tregs and an upregulation of FoxP3 mRNA expression in spleen and kidney. In vitro experiments showed that FTY720 induced expansion of Tregs, possibly via conversion from non-Tregs to Tregs. Depletion and adoptive transfer of Tregs were associated with loss and recovery of the beneficial effects of FTY720.Conclusion. These results suggest that the beneficial effects of FTY720 in I/R injury may be partially mediated by DC modulation or by increasing Treg activity. Further studies that identify tolerance induction mechanisms will be useful for developing strategies for the prevention or treatment of AKI.",
keywords = "acute kidney injury, dendritic cell, FTY720, regulatory T lymphocyte",
author = "Myung-Gyu Kim and Lee, {So Young} and Ko, {Yoon Sook} and Lee, {Hee Young} and Jo, {Sang Kyung} and Cho, {Won Yong} and Kim, {Hyoung Kyu}",
year = "2011",
month = "1",
day = "1",
doi = "10.1093/ndt/gfq480",
language = "English",
volume = "26",
pages = "111--124",
journal = "Nephrology Dialysis Transplantation",
issn = "0931-0509",
publisher = "Oxford University Press",
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T1 - CD4+ CD25+ regulatory T cells partially mediate the beneficial effects of FTY720, a sphingosine-1-phosphate analogue, during ischaemia/reperfusion-induced acute kidney injury

AU - Kim, Myung-Gyu

AU - Lee, So Young

AU - Ko, Yoon Sook

AU - Lee, Hee Young

AU - Jo, Sang Kyung

AU - Cho, Won Yong

AU - Kim, Hyoung Kyu

PY - 2011/1/1

Y1 - 2011/1/1

N2 - Background. The synthetic sphingosine-1-phosphate (S1P) analogue, FTY720, attenuates ischaemia/reperfusion (I/R) injury by inducing peripheral lymphopaenia. Recent studies suggest that FTY720 may also exert protective effects by modulating dendritic cell (DC) function or directly affecting regulatory T cells (Tregs). The purpose of the present study was to examine whether the beneficial effect of FTY720 in I/R-induced acute kidney injury (AKI) involves modulation of DCs or Tregs.Methods. Mice underwent bilateral ischaemia, and FTY720 or vehicle was then administered. Biochemical values, histological kidney damage and tissue inflammation were assessed. Phenotype and function of DCs in blood/spleen or kidney were also examined by flow cytometry or mixed lymphocyte reaction (MLR) assay. Percent Tregs or FoxP3 mRNA expression was examined in kidney and spleen, and depletion and adoptive transfer of Tregs were also performed.Results. Treatment with FTY720 attenuated I/R kidney injury and reduced inflammation. The beneficial effect of FTY720 was associated with expansion of peripheral CD11b+ CD11c+ DC and with maturation of spleen CD11c+ DC, which showed impaired allostimulatory capacity. FTY720-treated animals also showed a higher frequency of CD4 + CD25+ Tregs and an upregulation of FoxP3 mRNA expression in spleen and kidney. In vitro experiments showed that FTY720 induced expansion of Tregs, possibly via conversion from non-Tregs to Tregs. Depletion and adoptive transfer of Tregs were associated with loss and recovery of the beneficial effects of FTY720.Conclusion. These results suggest that the beneficial effects of FTY720 in I/R injury may be partially mediated by DC modulation or by increasing Treg activity. Further studies that identify tolerance induction mechanisms will be useful for developing strategies for the prevention or treatment of AKI.

AB - Background. The synthetic sphingosine-1-phosphate (S1P) analogue, FTY720, attenuates ischaemia/reperfusion (I/R) injury by inducing peripheral lymphopaenia. Recent studies suggest that FTY720 may also exert protective effects by modulating dendritic cell (DC) function or directly affecting regulatory T cells (Tregs). The purpose of the present study was to examine whether the beneficial effect of FTY720 in I/R-induced acute kidney injury (AKI) involves modulation of DCs or Tregs.Methods. Mice underwent bilateral ischaemia, and FTY720 or vehicle was then administered. Biochemical values, histological kidney damage and tissue inflammation were assessed. Phenotype and function of DCs in blood/spleen or kidney were also examined by flow cytometry or mixed lymphocyte reaction (MLR) assay. Percent Tregs or FoxP3 mRNA expression was examined in kidney and spleen, and depletion and adoptive transfer of Tregs were also performed.Results. Treatment with FTY720 attenuated I/R kidney injury and reduced inflammation. The beneficial effect of FTY720 was associated with expansion of peripheral CD11b+ CD11c+ DC and with maturation of spleen CD11c+ DC, which showed impaired allostimulatory capacity. FTY720-treated animals also showed a higher frequency of CD4 + CD25+ Tregs and an upregulation of FoxP3 mRNA expression in spleen and kidney. In vitro experiments showed that FTY720 induced expansion of Tregs, possibly via conversion from non-Tregs to Tregs. Depletion and adoptive transfer of Tregs were associated with loss and recovery of the beneficial effects of FTY720.Conclusion. These results suggest that the beneficial effects of FTY720 in I/R injury may be partially mediated by DC modulation or by increasing Treg activity. Further studies that identify tolerance induction mechanisms will be useful for developing strategies for the prevention or treatment of AKI.

KW - acute kidney injury

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