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Effects of Immunosuppressive Medications on Mitochondrial Function.

Publication ,  Journal Article
Nash, A; Samoylova, M; Leuthner, T; Zhu, M; Lin, L; Meyer, JN; Brennan, TV
Published in: The Journal of surgical research
May 2020

Immunosuppressive medications are widely used for the prevention of allograft rejection in transplantation and graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Despite their clinical utility, these medications are accompanied by multiple off-target effects, some of which may be mediated by their effects on mitochondria.We examined the effect of commonly used immunosuppressive reagents, mycophenolate mofetil (MMF), cyclosporine A (CsA), rapamycin, and tacrolimus on mitochondrial function in human T-cells. T-cells were cultured in the presence of immunosuppressive medications in a range of therapeutic doses. After incubation, mitochondrial membrane potential, reactive oxygen species (ROS) production, and apoptotic cell death were measured by flow cytometry after staining with DiOC6, MitoSOX Red, and Annexin V and 7-AAD, respectively. Increases in cytosolic cytochrome c were demonstrated by Western blot. T-cell basal oxygen consumption rates were measured using a Seahorse bioanalyzer.T-cells demonstrated significant levels of mitochondrial depolarization after treatment with therapeutic levels of MMF but not after treatment with CsA, tacrolimus, or rapamycin. Only MMF induced T-cell ROS production and induced significant levels of apoptotic cell death that were associated with increased levels of cytosolic cytochrome c. MMF decreased T-cell basal oxygen consumption within its therapeutic range, and CsA demonstrated a trend toward this result.The impairment of mitochondrial function by commonly used immunosuppressive reagents may impair T-cell differentiation and function by decreasing energy production, producing toxic ROS, and inducing apoptotic cell death.

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Published In

The Journal of surgical research

DOI

EISSN

1095-8673

ISSN

0022-4804

Publication Date

May 2020

Volume

249

Start / End Page

50 / 57

Related Subject Headings

  • Tacrolimus
  • T-Lymphocytes
  • Surgery
  • Sirolimus
  • Reactive Oxygen Species
  • Mycophenolic Acid
  • Mitochondria
  • Membrane Potential, Mitochondrial
  • Jurkat Cells
  • Immunosuppressive Agents
 

Citation

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Nash, A., Samoylova, M., Leuthner, T., Zhu, M., Lin, L., Meyer, J. N., & Brennan, T. V. (2020). Effects of Immunosuppressive Medications on Mitochondrial Function. The Journal of Surgical Research, 249, 50–57. https://doi.org/10.1016/j.jss.2019.12.010
Nash, Amanda, Mariya Samoylova, Tess Leuthner, Minghua Zhu, Liwen Lin, Joel N. Meyer, and Todd V. Brennan. “Effects of Immunosuppressive Medications on Mitochondrial Function.The Journal of Surgical Research 249 (May 2020): 50–57. https://doi.org/10.1016/j.jss.2019.12.010.
Nash A, Samoylova M, Leuthner T, Zhu M, Lin L, Meyer JN, et al. Effects of Immunosuppressive Medications on Mitochondrial Function. The Journal of surgical research. 2020 May;249:50–7.
Nash, Amanda, et al. “Effects of Immunosuppressive Medications on Mitochondrial Function.The Journal of Surgical Research, vol. 249, May 2020, pp. 50–57. Epmc, doi:10.1016/j.jss.2019.12.010.
Nash A, Samoylova M, Leuthner T, Zhu M, Lin L, Meyer JN, Brennan TV. Effects of Immunosuppressive Medications on Mitochondrial Function. The Journal of surgical research. 2020 May;249:50–57.
Journal cover image

Published In

The Journal of surgical research

DOI

EISSN

1095-8673

ISSN

0022-4804

Publication Date

May 2020

Volume

249

Start / End Page

50 / 57

Related Subject Headings

  • Tacrolimus
  • T-Lymphocytes
  • Surgery
  • Sirolimus
  • Reactive Oxygen Species
  • Mycophenolic Acid
  • Mitochondria
  • Membrane Potential, Mitochondrial
  • Jurkat Cells
  • Immunosuppressive Agents