Mycophenolic Acid-Induced GTP Depletion Also Affects Atp and Pyrimidine Synthesis in Mitogen-Stimulated Primary Human T-Lymphocytes1

Qiu, Yu; Fairbanks, L D; Rückermann, K; Hawrlowicz, C M; Richards, David F.; Kirschbaum, Bernhard J.; Simmonds, H. Anne

doi:10.1097/00007890-200003150-00038

Cited by 43 publications

(38 citation statements)

References 28 publications

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“…Similarly, it has been previously demonstrated that brequinar, an inhibitor of de novo pyrimidine synthesis, suppresses not only T cell proliferation, but also IL-2 receptor expression (22). The inhibition of mRNA synthesis because of the decrease in ATP, induced by either MMF or brequinar, may explain the suppression of CD25 expression (23,24). The fact that we only observed a rather weak inhibition of CD25 expression only at high MPA concentrations provides some circumstantial evidence for the utility of an additional anti-CD25 monoclonal antibody to sufficiently suppress acute rejection…”

Section: Discussionmentioning

confidence: 84%

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%

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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“…Other studies of Con A-stimulated human T lymphocytes show that MPA induces GTP depletion and decreases ATP pools, resulting in a lack of pyrimidine synthesis (29).…”

Section: Pharmacodynamics Of Mycophenolate Mofetilmentioning

confidence: 95%

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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“…Blockade of IMPDH by MPA was shown to deplete the guanosine (Gua) pool in lymphocytes (6) and to inhibit T and B cell proliferation, differentiation of alloreactive cytotoxic T cells, and Ab responses (7)(8)(9). More recently, MMF was shown to impair maturation of murine dendritic cells, suggesting that MMF can also affect APC functions (10).…”

Section: Ycophenolate Mofetil (Mmf)mentioning

confidence: 99%

“…More recently, MMF was shown to impair maturation of murine dendritic cells, suggesting that MMF can also affect APC functions (10). Inhibition of T lymphocyte proliferation was shown to result from a blockade of activated lymphocytes in early-to mid-G 1 phase of the cell cycle, resulting from a lack of induction of cyclin D/cyclin-dependent kinase (CDK) 6 and impaired degradation of the CDK inhibitor p27 Kip1 (9). Downregulation of the CDK inhibitor p27 Kip1 was shown to depend on the binding of IL-2 to its high-affinity trimeric receptor (11)(12)(13).…”

Section: Ycophenolate Mofetil (Mmf)mentioning

confidence: 99%

Mycophenolic Acid Inhibits IL-2-Dependent T Cell Proliferation, But Not IL-2-Dependent Survival and Sensitization to Apoptosis

Quéméneur¹,

Flacher²,

Gerland

et al. 2002

The Journal of Immunology

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Mycophenolic acid (MPA), the active metabolite of the immunosuppressive drug mycophenolate mofetil, is a selective inhibitor of inosine 5′-monophosphate dehydrogenase type II, a de novo purine nucleotide synthesis enzyme expressed in T and B lymphocytes and up-regulated upon cell activation. In this study, we report that the blockade of guanosine nucleotide synthesis by MPA inhibits mitogen-induced proliferation of PBL, an effect fully reversed by addition of guanosine and shared with mizoribine, another inhibitor of inosine 5′-monophosphate dehydrogenase. Because MPA does not inhibit early TCR-mediated activation events, such as CD25 expression and IL-2 synthesis, we investigated how it interferes with cytokine-dependent proliferation and survival. In activated lymphoblasts that are dependent on IL-2 or IL-15 for their proliferation, MPA does not impair signaling events such as of the extracellular signal-regulated kinase 2 and Stat5 phosphorylation, but inhibits down-regulation of the cyclin-dependent kinase inhibitor p27Kip1. Therefore, in activated lymphoblasts, MPA specifically interferes with cytokine-dependent signals that control cell cycle and blocks activated T cells in the mid-G1 phase of the cell cycle. Although it blocks IL-2-mediated proliferation, MPA does not inhibit cell survival and Bcl-xL up-regulation by IL-2 or other cytokines whose receptors share the common γ-chain (CD132). Finally, MPA does not interfere with IL-2-dependent acquisition of susceptibility to CD95-mediated apoptosis and degradation of cellular FLIP. Therefore, MPA has unique functional properties not shared by other immunosuppressive drugs interfering with IL-2R signaling events such as rapamycin and CD25 mAbs.

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Mycophenolic Acid-Induced GTP Depletion Also Affects Atp and Pyrimidine Synthesis in Mitogen-Stimulated Primary Human T-Lymphocytes1

Cited by 43 publications

References 28 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

Mycophenolic Acid Inhibits IL-2-Dependent T Cell Proliferation, But Not IL-2-Dependent Survival and Sensitization to Apoptosis

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