Effects of Immunosuppressive Medications on Mitochondrial Function, 2020, Nash et al

Andy · Jan 11, 2020

BACKGROUND:
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.

METHODS:
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.

RESULTS:
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.

CONCLUSIONS:
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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PubMed abstract, https://www.ncbi.nlm.nih.gov/pubmed/31918330 - link to published article on PubMed doesn't work yet.

Jaybee00 · Jan 11, 2020

CONCLUSIONS:
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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Except that this wasn't really the conclusion of their study. Based on reading the Results section of the abstract, the conclusion should be

"We found that of four commonly used immunosuppressive agents that we tested, only MMF depolarized mitochondria, induced T-cell ROS production and apoptotic cell death and decreased T-cell basal oxygen consumption. CsA, rapamycin, and tacrolimus had no significant effect on these parameters."

So their original conclusion is misleading IMO. Also did they really need to use both "impair/ment" and "producing/production" twice in that one sentence?

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Effects of Immunosuppressive Medications on Mitochondrial Function, 2020, Nash et al

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Effects of Immunosuppressive Medications on Mitochondrial Function, 2020, Nash et al

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