Pharmacodynamics of Mycophenolic Acid in Heart Allograft Recipients: Correlation of Lymphocyte Proliferation and Activation With Pharmacokinetics and Graft Histology1

Gummert, Jan; Barten, Markus J.; Gelder, Teun van; Billingham, Margaret E.; Morris, Randall E.

doi:10.1097/00007890-200010150-00009

Cited by 60 publications

(61 citation statements)

References 26 publications

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“…At this time point, CD25 and CD71 expression also significantly decreased, by 46% and 50%, respectively. According to a previous report by Gummert et al, the maximum efficacy of MPA (10,11) was lower for T cellactivation markers compared with T cell proliferation. In the present study, we similarly observed differences between the effective MPA concentrations.…”

Section: Discussionmentioning

confidence: 84%

“…In a rat heart-transplant model, both MPA (11) and MMF (12,13) therapies suppressed T cell proliferation and T cell-activation markers (CD25 and CD134). These effects correlated with MPA levels and the severity of histologic scores of rejection (11)(12)(13). In kidney-transplant patients, Sankatssing et al reported that MMF inhibits T cell proliferation without lowering intracellular dGTP (16).…”

Section: Discussionmentioning

confidence: 94%

“…Finally, similar to a previous report by Queneumer et al, who found in vitro that T cell proliferation was inhibited by the presence of MPA without a decrease of IL-2 level (15), we also did not observe a decrease in intralymphocyte IL-2 expression. The fact that MPA does not influence intracellular IL-2 production, provides some evidence that MPA has unspecific effects on all T cell activation processes Previous experiments had shown in vitro (8,10) and in vivo in nonhuman animal models that MMF (12,13) as well as its active metabolite (10), that is, MPA, has a high potency to inhibit T cell proliferation and lymphocyte surface-antigen expression. MPA dose-dependent inhibition of CD25 has been demonstrated (10 -12).…”

Section: Discussionmentioning

confidence: 99%

“…PD monitoring of MMF, by measuring IMPDH activity, has been previously performed in kidney transplant patients (9). The effect of MMF on T cell function has been assessed both in vitro (8) (10) and in vivo in a rat heart-transplant model (11)(12)(13). However, data regarding the effect of MMF on lymphocyte function in patients undergoing kidney transplantation are scarce.…”

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confidence: 99%

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Pharmacodynamic Evaluation of the First Dose of Mycophenolate Mofetil Before Kidney Transplantation

Kamar

Glander

Nolting

et al. 2009

Clinical Journal of the American Society of Nephrology

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Background and objectives: The effect of mycophenolate mofetil (MMF) on T cell function has not been evaluated in patients undergoing kidney transplantation. The aim of this study was to assess the effect of 1g of MMF on T cell function, that is, intralymphocyte cytokine expression, T cell activation (CD25 and CD71), and T cell proliferation, as well as inosine monophosphate dehydrogenase (IMPDH) activity, to better understand the relationship between pharmacokinetic and pharmacodynamic markers in patients receiving the first dose of MMF before kidney transplantation.Patients: Twenty-four patients undergoing a kidney transplantation from a living donor were enrolled in this study. Results: Compared with baseline (before MMF intake), T cell proliferation (93%), IMPDH activity (74%), CD25 (46%), and CD71 (50%) expression significantly decreased during the first hour after MMF intake, in parallel to the rise in MPA concentration. Thereafter, all pharmacodynamic markers, except IMPDH activity, returned back to baseline level. There was a complex inverse relationship between pharmacokinetic and pharmacodynamic markers. The inhibition of T cell proliferation was highly correlated to IMPDH activity, but also to T cell activation markers.Conclusion: The administration of MMF to patients is associated not only with a dramatic decrease in both T cell proliferation and IMPDH activity, but also with in a decrease in CD25 and CD71 expression.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Pharmacodynamic Evaluation of the First Dose of Mycophenolate Mofetil Before Kidney Transplantation

Kamar

Glander

Nolting

et al. 2009

Clinical Journal of the American Society of Nephrology

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“…Therefore, the coefficients of correlation between the AUE 0ª24 h and dose levels or plasma concentrations (AUC 0ª24 h ) are higher for S/G 2 M expression than the coefficients of correlation between AUE 0ª24 h and dose levels or AUC 0ª24 h [ 3 H]-TdR incorporation ( Table 2). The difference between [ 3 H]-TdR incorporation and flow cytometric measurements of lymphocyte proliferation can be explained by factors inherent to each technique as described previously (16).…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamics of Mycophenolate Mofetil after Heart Transplantation: New Mechanisms of Action and Correlations with Histologic Severity of Graft Rejection

Barten

Gelder

Gummert

et al. 2002

American Journal of Transplantation

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The primary mechanism of action in vivo of mycophenolate mofetil (MMF) is believed to be inhibition of lymphocyte proliferation. We used novel assays of lymphocyte functions (pharmacodynamics, PD) in whole blood collected from rat heart allograft recipients treated with MMF to investigate the mechanisms of action of the active metabolite of MMF, mycophenolate acid (MPA) in vivo. Allograft recipients were treated orally once daily with 3 different doses of MMF. Seven days after transplantation, blood was collected 24 h after the penultimate dose and several timepoints after the last dose, after which grafts were removed for microscopic grading of rejection. Lymphocytes in whole blood samples were mitogen stimulated through calcium-dependent and -independent signaling pathways. Inhibition of PD was measured by lymphocyte proliferation and expression of several surface antigens on T cells, and was calculated as area under the time-inhibition of immune function effect curve (AUE 0ª24 h ). We found that inhibition of lymphocyte proliferation and antigen expression by MPA correlated highly with MMF-dose, MPA level and with the histologic severities of graft rejection (p ∞0.05). In summary, MPA suppressed lymphocyte proliferation and expression of T-cell surface antigens in whole blood collected from MMF-treated allograft recipients, thus demonstrating the multiple mechanisms of suppression of rejection on peripheral blood T cells after MMF treatment.

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Whole blood flow cytometric measurement of NFATc1 and IL‐2 expression to analyze cyclosporine A‐mediated effects in T cells

et al. 2010

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The calcineurin inhibitor Cyclosporine A (CsA) is one of the crucial immunosuppressive drugs given after organ transplantation. The small therapeutic window of CsA generates the dilemma that efficient and toxic drug doses differ only slightly. Moreover, these threshold concentrations differ considerably between individuals; therefore, functional assays are urgently needed. We explored whether the transcription factor NFATc1, a direct as well as indirect target of CsA, can be used as a potential biomarker to determine the individual immunosuppressive activity of CsA. First, in isolated human T cells we showed that flow cytometry is practicable to measure NFATc1, the most abundant NFATc isoform in activated T cells. Second, for whole blood we developed a flow cytometric assay to determine in parallel the inducible transcription factor NFATc1 and the cytokine IL-2 in stimulated T cells. We found that added CsA inhibits both the expression of NFATc1 and IL-2 in T cells of stimulated whole blood samples with IC 50 values of 200 and 150 nM, respectively. The intra-and inter-assay variability was low, and clinical practicability was good. Further experiments have to demonstrate whether the parallel cytometric measurement of NFATc1 and IL-2 in whole blood is a good predictor of individual CsA efficacy and toxicity in CsA-treated patients. '

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Pharmacodynamics of Mycophenolic Acid in Heart Allograft Recipients: Correlation of Lymphocyte Proliferation and Activation With Pharmacokinetics and Graft Histology1

Abstract: MPA inhibits both lymphocyte proliferation and activation. PD by flow cytometry (FCM) correlates highly with severity of graft rejection, showing that PD of MPA measured in peripheral blood predicts immune cell activity in graft tissue.

Cited by 60 publications

References 26 publications

Pharmacodynamic Evaluation of the First Dose of Mycophenolate Mofetil Before Kidney Transplantation

Pharmacodynamic Evaluation of the First Dose of Mycophenolate Mofetil Before Kidney Transplantation

Pharmacodynamics of Mycophenolate Mofetil after Heart Transplantation: New Mechanisms of Action and Correlations with Histologic Severity of Graft Rejection

Whole blood flow cytometric measurement of NFATc1 and IL‐2 expression to analyze cyclosporine A‐mediated effects in T cells

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