Mycophenolate mofetil inhibits T-cell proliferation in kidney transplant recipients without lowering intracellular dGTP and GTP

Sankatsing, Sanjay U. C.; Prins, Jan M.; Yong, S. L.; Roelofsen, Jeroen; Kuilenburg, André B. P.; Kewn, Steve; Back, David; Bemelman, Fréderike J.; Berge, Ineke J. M. ten

doi:10.1111/j.1432-2277.2008.00739.x

Cited by 11 publications

(15 citation statements)

References 22 publications

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“…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). The present study, performed in uremic patients, further confirms and extends the observation that MPA not only inhibits IMPDH activity, but also influences T cell proliferation and activation.…”

Section: Discussionsupporting

confidence: 78%

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: Discussionsupporting

confidence: 78%

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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“…In a rat heart-transplant model, both MPA [32] and MMF [30,31] therapies suppressed T-cell proliferation and T-cell-activation markers (CD25 and CD134). In patients, it has been also recently shown that MPA does not only inhibit IMPDH activity, but also influences T-cell proliferation and activation [33,34]. Leflunomide inhibits lymphocyte proliferation by inhibiting pyrimidine synthesis [10,35].…”

Section: Discussionmentioning

confidence: 99%

Polyoma BK virus-associated nephropathy in kidney-transplant patients: Effects of leflunomide on T-cell functions and disease outcome

Canivet

Rostaing

Galvani

et al. 2009

International Immunopharmacology

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“…In both studies, IFNγ concentration was measured in the culture supernatant, and such concentration is strongly related to the number of cells present. Since proliferation decreases under the influence of MPA (18, 51), cytokine production should be corrected for cell numbers as we did by measuring intracellular IFNγ. In addition, Egli et al (50) did not measure T-cell specific IFNγ production and since NK cells are also capable of producing IFNγ this may have influenced their results.…”

Section: Discussionmentioning

confidence: 99%

Interferon-Gamma DNA Methylation Is Affected by Mycophenolic Acid but Not by Tacrolimus after T-Cell Activation

et al. 2017

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Immunosuppressive drug therapy is required to treat patients with autoimmune disease and patients who have undergone organ transplantation. The main targets of the immunosuppressive drugs tacrolimus and mycophenolic acid (MPA; the active metabolite of mycophenolate mofetil) are T cells. It is currently unknown whether these immunosuppressive drugs have an effect on DNA methylation—an epigenetic regulator of cellular function. Here, we determined the effect of tacrolimus and MPA on DNA methylation of the gene promoter region of interferon gamma (IFNγ), a pro-inflammatory cytokine. Total T cells, naive T cells (CCR7+CD45RO−), and memory T cells (CD45RO+ and CCR7−CD45RO−) were isolated from CMV seropositive healthy controls and stimulated with α-CD3/CD28 in the presence or absence of tacrolimus or MPA. DNA methylation of the IFNγ promoter region was quantified by pyrosequencing at 4 h, days 1, 3, and 4 after stimulation. In parallel, T-cell differentiation, and IFNγ protein production were analyzed by flow cytometry at days 1 and 3 after stimulation. Our results show that MPA induced changes in IFNγ DNA methylation of naive T cells; MPA counteracted the decrease in methylation after stimulation. Tacrolimus did not affect IFNγ DNA methylation of naive T cells. In the memory T cells, both immunosuppressive drugs did not affect IFNγ DNA methylation. Differentiation of naive T cells into a central-memory-like phenotype (CD45RO+) was inhibited by both immunosuppressive drugs, while differentiation of memory T cells remained unaffected by both MPA and tacrolimus. IFNγ protein production was suppressed by tacrolimus. Our results demonstrate that MPA influenced IFNγ DNA methylation of naive T cells after stimulation of T cells, while tacrolimus had no effect. Both tacrolimus and MPA did not affect IFNγ DNA methylation of memory T cells.

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Mycophenolate mofetil inhibits T-cell proliferation in kidney transplant recipients without lowering intracellular dGTP and GTP

Cited by 11 publications

References 22 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

Polyoma BK virus-associated nephropathy in kidney-transplant patients: Effects of leflunomide on T-cell functions and disease outcome

Interferon-Gamma DNA Methylation Is Affected by Mycophenolic Acid but Not by Tacrolimus after T-Cell Activation

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