Pharmacodynamic effect of mTOR inhibition-based immunosuppressive therapy on dendritic cell and natural killer cell subsets after renal transplantation.

BACKGROUND

mTOR inhibitor therapy is solely monitored via pharmacokinetics after kidney transplantation, which may not accurately reflect the effectiveness of PI3K-Akt-mTOR pathway blockade, potentially leading to inadequate or excessive immunosuppression. The pharmacodynamic effect of mTOR inhibition on natural killer (NK) cells and dendritic cell (DC) subsets after renal transplantation has not been investigated so far.

METHODS

Phosphoflow cytometry was employed in this cross-sectional study to evaluate the extent of mTOR inhibition in peripheral DC and NK cell subsets by assessing p70S6 kinase phosphorylation in kidney transplant recipients treated with mTOR inhibitors either in combination with calcineurin inhibitors (mTORi + CNI, n = 17) or mycophenolate sodium (mTORi + MPA, n = 9). The control group comprised nine end-stage renal disease patients undergoing dialysis therapy and 17 healthy volunteers.

RESULTS

mTOR inhibitor-based therapy significantly reduced p70S6K phosphorylation levels in CD3-CD56+ NK cells compared to healthy controls, while p70S6K phosphorylation among HLA-DR+ Lin- total DCs was not different. In comparison to mTORi + MPA therapy, renal transplant patients receiving mTORi + CNI treatment exhibited a stronger inhibition of p70S6K phosphorylation in HLA-DR+ Lin- total DCs, CD123+CD11c- plasmacytoid DCs, CD123-CD11c+ myeloid DCs, and CD16-CD56bright NK cells. However, the serum trough levels of mTORi showed no correlation with p70S6K phosphorylation levels in all investigated cell subsets.

CONCLUSION

mTORi selectively suppressed p70S6K phosphorylation in specific DC and NK subtypes. Evaluating p70S6K phosphorylation through phosphoflow cytometry might serve as a clinically applicable method to comprehend immune cell subset-specific effects of mTOR inhibition, providing detailed pharmacodynamic insights for tailoring mTORi therapy on an individual basis.