Long-Term Redistribution of Peripheral Lymphocyte Subpopulations after Switching from Calcineurin to mTOR Inhibitors in Kidney Transplant Recipients

Llinàs‐Mallol, Laura; Redondo-Pachón, Dolores; Raïch‐Regué, Dàlia; Pérez‐Sáez, María José; Yélamos, José; Duran, Xavier; Faura, Anna; López‐Botet, Miguel; Pascual, Julio; Crespo, Marta

doi:10.3390/jcm9041088

Cited by 7 publications

(2 citation statements)

References 64 publications

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“…Consistently, studies demonstrated inhibition of proliferation and induction of apoptosis of Th cells as well as a selectively expansion of Treg upon mTORi treatment in vivo or in vitro. [22][23][24] In line, we here demonstrated a suppression of p70S6K phosphorylation in CD4 + CD45RA -CD25 − Th cells by mTORi, while CD4 + CD45RA -CD25 ++ CD127 − Treg remained unaffected. The latter reflect their independence from mTOR signaling (Figure 4).…”

Section: Discussionsupporting

confidence: 83%

Pharmacodynamic Effect of mTOR Inhibition-based Immunosuppressive Therapy on T- and B-cell Subsets After Renal Transplantation

Wei,

Weber,

Yin

et al. 2024

Transplantation Direct

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Background. The mammalian target of rapamycin inhibitor (mTORi) therapy after kidney transplantation is solely monitored pharmacokinetically, not necessarily reflecting PI3K-Akt-mTOR pathway blockade efficacy leading to potential under-or overimmunosuppression. Methods. In this cross-sectional study, phosphoflow cytometry was used to determine the efficacy of mTOR inhibition in peripheral T- and B-lymphocyte subsets by assessing p70S6 kinase (p70S6K) phosphorylation in renal transplant recipients upon treatment with a combination of either mTORi and calcineurin inhibitors (n = 18), or mTORi with mycophenolic acid (n = 9). Nine dialysis patients with end-stage renal disease and 17 healthy age-matched volunteers served as controls. Results. mTORi treatment reduced p70S6K phosphorylation in CD4+, CD8+ T, and CD19+ B cells compared with healthy controls (HCs). Subpopulation analysis of CD4+ T cells and CD19+ B cells revealed a significant reduction of p70S6K phosphorylation in CD4+CD45RA−CD25− Th cells (P < 0.05), CD24hiCD38hi transitional B cells (P < 0.001), CD24+CD38− memory B cells (P < 0.001), and CD24intCD38int-naive B cells (P < 0.05) upon mTORi treatment, whereas CD4+CD45RA−CD25++CD127− regulatory T cells and CD24−CD38hi plasmablasts were not affected. Compared with mTORi + mycophenolic acid therapy, mTORi + calcineurin inhibitor treatment exhibited an even stronger inhibition of p70S6K phosphorylation in CD4+CD45RA−CD25− Th cells and CD8+ T cells. However, trough levels of mTORi did not correlate with p70S6K phosphorylation. Conclusions. mTORi selectively inhibited p70S6K phosphorylation in select lymphocyte subtypes. Assessing p70S6K phosphorylation by phosphoflow cytometry may serve as an approach to understand cell subset specific effects of mTORi providing detailed pharmacodynamic information for individualizing immunosuppression.

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Section: Discussionsupporting

confidence: 83%

Pharmacodynamic Effect of mTOR Inhibition-based Immunosuppressive Therapy on T- and B-cell Subsets After Renal Transplantation

Wei,

Weber,

Yin

et al. 2024

Transplantation Direct

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“…For example, FK-506 is often treated with MMF in kidney transplantation. Based on individual differences, other treatment regimens include FK-506/EVR/prednisolone (Perd), FK-506/mycophenolic acld (MPA)/Perd triple regimens, and FK-506/EVR double regimens [18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Simultaneous Determination of Six Immunosuppressants in Human Whole Blood by HPLC-MS/MS Using a Modified QuEChERS Method

et al. 2022

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A high-performance liquid chromatography-tandem mass spectrometry method was established for the simultaneous determination of mycophenolic acid, mycophenolate mofetil, tacrolimus, rapamycin, everolimus and pimecrolimus in human whole blood by optimizing the QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) preparation method. Whole blood was extracted into ethyl acetate, salted out with anhydrous magnesium sulfate, and purified with ethylenediamine-N-propyl silane adsorbent. The supernatant was evaporated under nitrogen until dry and finally reconstituted in methanol. Chromatographic separation was performed on an Agilent Poroshell 120 EC-C18 column in methanol (mobile phase A)-water (optimized for 0.1% acetic acid and 10 mM ammonium acetate, mobile phase B) at a 0.3 mL·min−1 flow rate. Electrospray ionization and positive ion multiple reaction monitoring were used for detection. The time for of analysis was 13 min. The calibration curves range of tacrolimus, rapamycin, everolimus and pimecrolimus were in the range of 1–100 ng·mL−1, mycophenolate mofetil in the range of 0.1–10 ng·mL−1 and mycophenolic acid at 10–1000 ng·mL−1. All correlation coefficients were >0.993. The coefficients of variation (CV, %) for inter-day and intra-day precision were less than 10%, while the spiked recoveries were in the range of 92.1% to 116%. Our method was rapid, sensitive, specific, and reproducible for the simultaneous determination of six immunosuppressants in human whole blood. Importantly, our approach can be used to monitor drug concentrations in the blood to facilitate disease treatment.

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Targeting regulatory T cell metabolism in disease: Novel therapeutic opportunities

2023

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Regulatory T cells (Tregs) are essential for immune homeostasis and suppression of pathological autoimmunity but can also play a detrimental role in cancer progression via inhibition of anti‐tumor immunity. Thus, there is broad applicability for therapeutic Treg targeting, either to enhance function, for example, through adoptive cell therapy (ACT), or to inhibit function with small molecules or antibody‐mediated blockade. For both of these strategies, the metabolic state of Tregs is an important consideration since cellular metabolism is intricately linked to function. Mounting evidence has shown that targeting metabolic pathways can selectively promote or inhibit Treg function. This review aims to synthesize the current understanding of Treg metabolism and discuss emerging metabolic targeting strategies in the contexts of transplantation, autoimmunity, and cancer. We discuss approaches to gene editing and cell culture to manipulate Treg metabolism during ex vivo expansion for ACT, as well as in vivo nutritional and pharmacological interventions to modulate Treg metabolism in disease states. Overall, the intricate connection between metabolism and phenotype presents a powerful opportunity to therapeutically tune Treg function.

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Long-Term Redistribution of Peripheral Lymphocyte Subpopulations after Switching from Calcineurin to mTOR Inhibitors in Kidney Transplant Recipients

Cited by 7 publications

References 64 publications

Pharmacodynamic Effect of mTOR Inhibition-based Immunosuppressive Therapy on T- and B-cell Subsets After Renal Transplantation

Pharmacodynamic Effect of mTOR Inhibition-based Immunosuppressive Therapy on T- and B-cell Subsets After Renal Transplantation

Simultaneous Determination of Six Immunosuppressants in Human Whole Blood by HPLC-MS/MS Using a Modified QuEChERS Method

Targeting regulatory T cell metabolism in disease: Novel therapeutic opportunities

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