Inhibitory Effect of Tacrolimus on p38 Mitogen-Activated Protein Kinase Signaling in Kidney Transplant Recipients Measured by Whole-Blood Phosphospecific Flow Cytometry

Vafadari, Ramin; Hesselink, Dennis A.; Cadogan, Monique; Weimar, Willem; Baan, Carla C.

doi:10.1097/tp.0b013e318250fc62

Cited by 19 publications

(13 citation statements)

References 31 publications

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“…It was recently discovered that Tac also suppresses the phosphorylation of the mitogen-activated protein kinase (MAPK) pathway [135]. The amount of phosphorylation of this signaling molecule seems to be inversely correlated with Tac C 0 in kidney transplant patients.…”

Section: Phosphospecific Flow Cytometrymentioning

confidence: 99%

Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients

Andrews

Winter

et al. 2017

Expert Opinion on Drug Metabolism & Toxicology

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115

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Introduction: Tacrolimus (Tac) is the cornerstone of immunosuppressive therapy after solid organ transplantation and will probably remain so. Excluding belatacept, no new immunosuppressive drugs were registered for the prevention of acute rejection during the last decade. For several immunosuppressive drugs, clinical development halted because they weren't sufficiently effective or more toxic. Areas covered: Current methods of monitoring Tac treatment, focusing on traditional therapeutic drug monitoring (TDM), controversies surrounding TDM, novel matrices, pharmacogenetic and pharmacodynamic monitoring are discussed. Expert opinion: Due to a narrow therapeutic index and large interpatient pharmacokinetic variability, TDM has been implemented for individualization of Tac dose to maintain drug efficacy and minimize the consequences of overexposure. The relationship between predose concentrations and the occurrence of rejection or toxicity is controversial. Acute cellular rejection also occurs when the Tac concentration is within the target range, suggesting that Tac whole blood concentrations don't necessarily correlate with pharmacological effect. Intracellular Tac, the unbound fraction of Tac or pharmacodynamic monitoring could be better biomarkers/tools for adequate Tac exposure -research into this has been promising. Traditional TDM, perhaps following pre-emptive genotyping for Tac-metabolizing enzymes, must suffice for a few years before these strategies can be implemented in clinical practice. ARTICLE HISTORY

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Section: Phosphospecific Flow Cytometrymentioning

confidence: 99%

Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients

Andrews

Winter

et al. 2017

Expert Opinion on Drug Metabolism & Toxicology

Self Cite

115

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“…CCL8 expression depends on transcription factor phosporylation by the mitogen‐activated protein kinases ERK 1/2 and p38 , which occurs following IFN‐γ stimulation in monocytic THP‐1 cells . This can be inhibited by tacrolimus and mycophenolic acid . Posttranscriptional regulation of IFN‐γ‐induced transcript stability is also dependent on such enzymes , with evidence indicating a faster decay of mRNA transcripts in association with calcineurin inhibitors and rapamycin .…”

Section: Discussionmentioning

confidence: 99%

CCL8 and the Immune Control of Cytomegalovirus in Organ Transplant Recipients

Lisboa

Egli

Fairbanks

et al. 2015

American Journal of Transplantation

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y Shared senior authorship.Monitoring of cytomegalovirus cell-mediated immunity is a promising tool for the refinement of preventative and therapeutic strategies posttransplantation. Typically, the interferon-g response to T cell stimulation is measured. We evaluated a broad range of cytokine and chemokines to better characterize the ex vivo hostresponse to CMV peptide stimulation. In a cohort of CMV viremic organ transplant recipients, chemokine expression-specifically CCL8 (AUC 0.849 95% CI 0.721-0.978; p ¼ 0.003) and CXCL10 (AUC 0.841, 95% CI 0.707-0.974; p ¼ 0.004)-was associated with control of viral replication. In a second cohort of transplant recipients at high-risk for CMV, the presence of a polymorphism in the CCL8 promoter conferred an increased risk of viral replication after discontinuation of antiviral prophylaxis (logrank hazard ratio 3.6; 95% CI 2.077-51.88). Using cell-sorting experiments, we determined that the primary cell type producing CCL8 in response to CMV peptide stimulation was the monocyte fraction. Finally, in vitro experiments using standard immunosuppressive agents demonstrated a dose-dependent reduction in CCL8 production. Chemokines appear to be important elements of the cellmediated response to CMV infection posttransplant, as here suggested for CCL8, and translation of this knowledge may allow for the tailoring and improvement of preventative strategies.

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“…However, in patients treated with the less selective immunosuppressive agent neoral, IL‐2 production is inhibited via blockade of all major signalling pathways, i.e. NFAT, p38 and NF‐κB1 . Another explanation for ‘Treg sparing’ might be the differential signalling cascades downstream of the IL‐2 receptor activation.…”

Section: Discussionmentioning

confidence: 99%

The protein kinase C inhibitor sotrastaurin allows regulatory T cell function

Weerd

Kho

Kraaijeveld

et al. 2014

Clinical and Experimental Immunology

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SummaryThe novel immunosuppressant sotrastaurin is a selective inhibitor of protein kinase C isoforms that are critical in signalling pathways downstream of the T cell receptor. Sotrastaurin inhibits nuclear factor (NF)-κB, which directly promotes the transcription of forkhead box protein 3 (FoxP3), the key regulator for the development and function of regulatory T cells (Tregs). Our center participated in a randomized trial comparing sotrastaurin (n = 14) and the calcineurin inhibitor Neoral (n = 7) in renal transplant recipients. We conducted ex vivo mixed lymphocyte reaction (MLR) and flow cytometry studies on these patient samples, as well as in vitro studies on samples of blood bank volunteers (n = 38). Treg numbers remained stable after transplantation and correlated with higher trough levels of sotrastaurin (r = 0·68, P = 0·03). A dose-dependent effect of sotrastaurin on alloresponsiveness was observed: the half maximal inhibitory concentration (IC50) to inhibit alloactivated T cell proliferation was 45 ng/ml (90 nM). In contrast, Treg function was not affected by sotrastaurin: in the presence of in vitro-added sotrastaurin (50 ng/ml) Tregs suppressed the proliferation of alloactivated T effector cells at a 1:5 ratio by 35 versus 47% in the absence of the drug (P = 0·33). Signal transducer and activator of transcription 5 (STAT)-5 phosphorylation in Tregs remained intact after incubation with sotrastaurin. This potent Treg function was also found in cells of patients treated with sotrastaurin: Tregs inhibited the anti-donor response in MLR by 67% at month 6, which was comparable to pretransplantation (82%). Sotrastaurin is a potent inhibitor of alloreactivity in vitro, while it did not affect Treg function in patients after kidney transplantation.

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Inhibitory Effect of Tacrolimus on p38 Mitogen-Activated Protein Kinase Signaling in Kidney Transplant Recipients Measured by Whole-Blood Phosphospecific Flow Cytometry

Abstract: TAC inhibits activation of the MAPK pathway in a dose-dependent manner in kidney transplant patients and may be a potential marker for immune monitoring.

Cited by 19 publications

References 31 publications

Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients

Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients

CCL8 and the Immune Control of Cytomegalovirus in Organ Transplant Recipients

The protein kinase C inhibitor sotrastaurin allows regulatory T cell function

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