Pretransplant Pharmacodynamic Analysis of Immunosuppressive Agents Using CFSE-Based T-Cell Proliferation Assay

Kurata, Yoko; Kato, Mayumi; Kuzuya, Takafumi; Miwa, Yuko; Iwasaki, Katsurô; Haneda, Masataka; Amioka, Katsuo; Watarai, Yoshihiko; Uchida, Kazuharu; Nakao, Akimasa; Kobayashi, Takaaki

doi:10.1038/clpt.2009.61

Cited by 19 publications

(14 citation statements)

References 27 publications

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“…Tirona and colleagues have identified OATP1B1 (SLCO1B1) as a liver-specific uptake transporter for statins, carrying frequent singlenucleotide polymorphisms with impaired function. 3 These findings translate into changes of pharmacokinetics in vivo (i.e., increased systemic concentrations as a consequence of reduced liver uptake), especially in individuals harboring the frequent c.SLCO1B1 521C→T polymorphism, which is associated with reduced function. Pharmacokinetic consequences of this polymorphism are important but rather modest, and they translate into only minor effects involving LDL reduction.…”

Section: Conflict Of Interestmentioning

confidence: 99%

“…2 These new entrants include the incretin-based therapies (e.g., GLP-1 analogs such as exenatide and liraglutide); DPP4 inhibitors such as sitagliptin, vildagliptin, and saxagliptin; glucokinase activators such as piragliatin, LY2121260, and GKA-50; and FGF21 mimetics. 3 Given the diversity of mechanisms of action and the range of target perspec tives possible relationships between the various outcome measures (e.g., adiponectin and HbA1c). This approach is superior to the common practice of examining only study-level data by meta-regression.…”

Section: Biomarkers Linked To Patient Outcomes (Safety and Efficacy) mentioning

confidence: 99%

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A Piece in the Puzzle of Personalized Medicine

Kroemer

Meyer

Schwabedissen

2010

Clin Pharmacol Ther

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Predicting individual drug response based on inherited factors remains a major challenge. Some examples of significant contributions of single genetic variants to overall therapeutic success of drugs in complex diseases are currently emerging. For most compounds, however, multiple genetic and nongenetic factors will modify drug action. Comprehensive integration of these factors will determine the role of pharmacogenomics for personalized medicine.

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Section: Conflict Of Interestmentioning

confidence: 99%

Section: Biomarkers Linked To Patient Outcomes (Safety and Efficacy) mentioning

confidence: 99%

A Piece in the Puzzle of Personalized Medicine

Kroemer

Meyer

Schwabedissen

2010

Clin Pharmacol Ther

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“…Several approaches have been evaluated to measure the biological effect of Tac and CsA: drug‐specific pharmacodynamic biomarkers, such as measurement of calcineurin phosphatase activity, nuclear translocation of nuclear factor of activated T cells (NFAT), amplification of NFATc1 and NFAT‐regulated gene expression (NFAT‐RGE), and other non‐specific biomarkers, such as intracellular cytokines . T cell proliferation and surface activation markers …”

Section: Introductionmentioning

confidence: 99%

“…11,12 T cell proliferation and surface activation markers. 13,14 It is well known that CNi inhibits NFAT translocation to the nucleus in CD4 + and CD8 + T cells, reducing the transcription of the genes it regulates, including interleukin-2 (IL-2), interferon-gamma (IFN-γ) and granulocyte macrophage colony-stimulating factor (GM-CSF); these changes in transcription modulate the alloimmune response against the implanted graft. 15,16 Focusing on the analysis of residual NFAT-RGE, several studies carried out in stable kidney transplant recipients have shown an inverse correlation between Tac or CsA blood concentrations and NFAT-RGE of IL-2, IFN-γ and GM-CSF 10,17,18 Results from a single randomized prospective interventional study (EudraCT 2011-003547-21) conducted in stable kidney transplant recipients 19 showed that reducing the CsA doses, and therefore the drug exposure, according to the NFAT-RGE results could be a useful tool to reduce cardiovascular risk compared with standard dose adjustment based on CsA trough levels.…”

Section: Introductionmentioning

confidence: 99%

Nuclear factor of activated T cells as potential pharmacodynamic biomarker for the risk of acute and subclinical rejection in de novo liver recipients

Millán

Ruíz

Fortuna

et al. 2020

Liver International

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Background & Aims Nuclear factor of activated T cell‐regulated gene expression (NFAT‐RGE) has been proposed as a pharmacodynamic biomarker for tacrolimus (Tac) and cyclosporine (CsA). Our aim was to evaluate the role of NFAT‐RGE in modulating intralymphocytary IL‐2 and IFN‐γ expression and its clinical utility as an early non‐invasive predictive biomarker for the risk of acute rejection (AR) and infection in de novo liver transplant (LT) recipients. Methods Fifty‐six LT recipients treated with Tac or CsA [with and without mycophenolate mofetil (MMF)] were included: 30 free of rejection or infection, 11 rejectors (T cell‐mediated acute rejection), 5 with subclinical rejection (SCR) and 10 with cytomegalovirus (CMV) infection. Within the first 3 months after transplantation, NFAT‐RGE of IL‐2, IFN‐γ and GM‐CSF and intralymphocytary synthesis of IL‐2 and IFN‐γ were evaluated by real‐time PCR and flow cytometry respectively. Results A significant increase in NFAT‐RGE was observed in patients who experienced TCMAR (75% [42–100%]) or SCR (41% [18–78%]) compared with patients without rejection or infection (14% [2–23%]). Positive correlations between the %NFAT‐RGE‐IFN and both the %CD8CD69IFN‐γ and %CD4CD69IFN‐γ and between the %NFAT‐RGE‐IL2 and the %CD8CD69IL2 were observed. NFAT‐RGE was significantly lower in CMV+ patients than in non‐infected patients. Finally, an inverse correlation between the Tac or CsA concentration and inhibition of NFAT‐RGE were observed. Conclusions Sequential post‐transplantation NFAT‐RGE monitoring combined with intralymphocytary IL‐2 and IFN‐γ before transplantation and at the first and third month post‐transplantation may be key predictive and diagnostic biomarkers for the risk of TCMAR and SCR and better guide CNi therapy in LT patients.

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“…Our previous study indicated that CSA and prednisolone had considerable inter-individual variation in their inhibitory effects on T-cell proliferation. 25) A more recent study demonstrated that CMV reactivation and acute T-cell mediated rejection were significantly associated with the CSA sensitivity of lymphocytes. 26) These studies suggested that not only the drug concentration in lymphocytes, but also the drug sensitivity affecting lymphocyte proliferation could influence the clinical outcome.…”

Section: )mentioning

confidence: 99%

Changes in ABCB1 mRNA Expression in Peripheral Blood Cells before and after Renal Transplantation

Kushihara

Kuzuya

Miwa

et al. 2016

Biological & Pharmaceutical Bulletin

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Cyclosporine (CSA), which is one of the substrates of ATP binding cassette subfamily B member 1 (ABCB1), is widely used as an immunosuppressant in patients undergoing transplantation. The expression level of P-glycoprotein on lymphocytes that is encoded by ABCB1 gene is considered to be one of the major causes of differences in intracellular CSA concentration. The clinical relevance of ABCB1 mRNA expression in peripheral blood was analyzed. We examined (i) the relationship between ABCB1 mRNA and the intracellular concentration of CSA in vitro, (ii) the change in long-term ABCB1 mRNA expression levels, and (iii) its association with acute rejection (AR) or cytomegalovirus (CMV) reactivation in living-donor renal transplantation. A significantly negative correlation between ABCB1 mRNA expression and intracellular CSA concentration in vitro was obtained (p<0.05). ABCB1 mRNA expression was significantly reduced (55%) 1 week after transplantation (p<0.001) and returned to the pre-transplantation level after 1 year. Although the sample size may be too small to obtain a definitive conclusion, no association was observed between ABCB1 mRNA expression levels and AR or CMV reactivation. Key words ATP binding cassette subfamily B member 1 (ABCB1); mRNA; renal transplantation; cyclosporine A P-Glycoprotein (P-gp) is encoded by the ATP binding cassette subfamily B member 1 (ABCB1, also known as multidrug resistance protein 1 (MDR1)) gene. This membrane protein functions as an energy-dependent drug efflux pump and reduces the intracellular concentrations of a wide range of drugs. P-gp was first identified as a surface phosphoglycoprotein expressed in drug resistant tumor cells, and its expression has been correlated with failed chemotherapeutic treatment and poor prognosis.

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Pretransplant Pharmacodynamic Analysis of Immunosuppressive Agents Using CFSE-Based T-Cell Proliferation Assay

Cited by 19 publications

References 27 publications

A Piece in the Puzzle of Personalized Medicine

A Piece in the Puzzle of Personalized Medicine

Nuclear factor of activated T cells as potential pharmacodynamic biomarker for the risk of acute and subclinical rejection in de novo liver recipients

Changes in ABCB1 mRNA Expression in Peripheral Blood Cells before and after Renal Transplantation

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