Everolimus and sirolimus antagonize tacrolimus based calcineurin inhibition via competition for FK-binding protein 12

Rossum, Huub H. van; Romijn, Fred P.H.T.M.; Smit, Nico P.M.; Fijter, Johan W. de; Pelt, Johannes van

doi:10.1016/j.bcp.2008.12.009

Cited by 35 publications

(27 citation statements)

References 17 publications

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“…mRNA levels of COX-1 and COX-2 were measured by RT-PCR (b As to the mechanisms of their action, we provided evidence that steroids inhibit the functions of T and B cells at low concentrations (10-50 nM), and inhibit COX-2 production by macrophages at high concentrations (1-10 lM). Calcineurin inhibitors cyclosporine A and tacrolimus are T cell-specific immunosuppressants (van Rossum et al 2009). We found that these drugs inhibit T cell proliferation at low non-toxic concentrations (10-30 nM), whereas they inhibit B cell proliferation and NO production in macrophages at much high micromolar concentrations.…”

Section: Discussionmentioning

confidence: 99%

Validation of cyclooxygenase-2 as a direct anti-inflammatory target of 4-O-methylhonokiol in zymosan-induced animal models

et al. 2014

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4-O-methylhonokiol (MH) is known to inhibit inflammation by partially understood mechanisms. Here, the anti-inflammatory mechanisms of MH were examined using enzymatic, cellular, and animal assays. In enzymatic assays, MH inhibited COX-2 activity with an IC50 of 0.062 μM, and also COX-1 with an IC50 of 2.4 μM. In cellular assays, MH was immunotoxic above 10 μM. At non-toxic concentrations (below 3 μM), MH strongly inhibited COX-2-mediated prostaglandin production with an IC50 of 0.1 μM, whereas did not or slightly affect other functions of B cells, T cells, dendritic cells, and macrophages. In an animal model, MH inhibited the increase in footpad thickness and popliteal lymph node weight in zymosan-injected mice. When analyzed the draining pLNs of zymosan-injected mice on day 5, MH inhibited the overall inflammatory responses. However, MH inhibited cyclooxygenase (COX)-2-mediated prostaglandin production without affecting tumor necrosis factor-α production in inflamed tissues within 6 h after zymosan injection. In summary, our data suggest that COX-2 may be a direct anti-inflammatory target of MH in vitro and in vivo.

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Section: Discussionmentioning

confidence: 99%

Validation of cyclooxygenase-2 as a direct anti-inflammatory target of 4-O-methylhonokiol in zymosan-induced animal models

et al. 2014

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“…This enzyme is selectively targeted by CNIs and can therefore be used to monitor the pharmacodynamics of Tac [113]. Van Rossum et al published a comprehensive review on this topic in which the pros and cons of this assay were extensively discussed [114].…”

Section: Calcineurin Activitymentioning

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

111

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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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“…For example, dose-dependent CNi-mediated antagonism of mTORi effects has been reported for mouse T cells 61 and for mouse and human alloprimed B cells 14,17 . The competitive inhibition between mTORi and CNi has been attributed to saturation of FK506-binding protein 12 62 . There is some evidence for this antagonism in our data.…”

Section: Discussionmentioning

confidence: 99%

mTOR Inhibition Suppresses Posttransplant Alloantibody Production Through Direct Inhibition of Alloprimed B Cells and Sparing of CD8+ Antibody-Suppressing T cells

et al. 2016

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Background De novo alloantibodies (DSA) contribute to antibody-mediated rejection and poor long-term graft survival. Since the development of DSA is associated with early graft loss of cell transplants and reduced long-term survival of solid organ transplants, we hypothesized that conventional immunosuppressives, calcineurin inhibitors (CNi) and mammalian target of rapamycin inhibitors (mTORi), may not be as effective for suppression of humoral alloimmunity as for cell-mediated immunity. Methods Wild-type or CD8-depleted mice were transplanted with allogeneic hepatocytes. Recipients were treated with mTORi and/or CNi and serially monitored for alloantibody and graft survival. The direct effect of mTORi and CNi on alloprimed B cell function was investigated in Rag1-/- mice adoptively transferred with alloprimed IgG1+ B cells. The efficacy of mTORi and/or CNi to suppress CD8-mediated cytotoxicity of IgG1+ B cells was evaluated in in vitro and in vivo cytotoxicity assays. Results mTORi, but not CNi, reduced alloantibody production in transplant recipients, directly suppressed alloantibody production by alloprimed IgG1+ B cells and delayed graft rejection in both low and high alloantibody-producers. Combination treatment with mTORi and CNi resulted in loss of the inhibitory effect observed for mTORi monotherapy in part due to CNi-suppression of CD8+ T cells which downregulate alloantibody production (CD8+ TAb-supp cells). Conclusions Our data supports that mTORi is a potent inhibitor of humoral immunity through suppression of alloprimed B cells and preservation of CD8+ TAb-supp cells. In contrast, alloantibody is readily detected in CNi-treated recipients because CNi does not suppress alloprimed B cells and interferes with downregulatory CD8+ TAb-supp cells.

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Everolimus and sirolimus antagonize tacrolimus based calcineurin inhibition via competition for FK-binding protein 12

Cited by 35 publications

References 17 publications

Validation of cyclooxygenase-2 as a direct anti-inflammatory target of 4-O-methylhonokiol in zymosan-induced animal models

Validation of cyclooxygenase-2 as a direct anti-inflammatory target of 4-O-methylhonokiol in zymosan-induced animal models

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

mTOR Inhibition Suppresses Posttransplant Alloantibody Production Through Direct Inhibition of Alloprimed B Cells and Sparing of CD8+ Antibody-Suppressing T cells

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