移植及开始免疫抑制后IMPDH1和IMPDH2的表达。
Expression of IMPDH1 and IMPDH2 after transplantation and initiation of immunosuppression.
作者信息
Bremer Sara, Mandla Randeep, Vethe Nils T, Rasmussen Ingrid, Rootwelt Helge, Line Pål-D, Midtvedt Karsten, Bergan Stein
机构信息
Department of Medical Biochemistry, Rikshospitalet Medical Centre, Institute of Clinical Biochemistry, University of Oslo, Norway.
出版信息
Transplantation. 2008 Jan 15;85(1):55-61. doi: 10.1097/01.tp.0000296854.68123.03.
BACKGROUND
Mycophenolic acid (MPA) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase (IMPDH). Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy. Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated.
METHODS
Whole blood, CD4+ cell, and reticulocyte samples were collected from 30 renal transplant patients pre- and posttransplantation. The expressions of two IMPDH isoforms, type 1 and 2, were analyzed by real-time reverse-transcription polymerase chain reaction and quantified using a housekeeping gene index. The IMPDH activity was determined by ultraviolet high-performance liquid chromatography.
RESULTS
Transplantation and the initiation of immunosuppressive therapy was associated with increased IMPDH1 (50-88%, P<0.0005) and decreased IMPDH2 (42-56%, P<0.0005) expression. In CD4+ cells, however, IMPDH2 increased (15%, P=0.009). These changes are probably related to glucocorticoid effects. Two weeks posttransplant, MPA-treated patients displayed elevated IMPDH 1 and 2 in reticulocytes, suggesting enzyme induction in these cells during prolonged MPA therapy. Patients with acute rejection during follow-up demonstrated higher IMPDH2 expression in CD4+ cells pretransplant than nonrejecting patients (median expression 1.26 vs. 0.87 respectively, P=0.017).
CONCLUSIONS
Knowledge of changes in IMPDH 1 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of MPA on IMPDH and the potential for pharmacodynamic monitoring of MPA by measuring IMPDH activity. The expression of IMPDH2 in CD4+ cells pretransplant may be an indicator of immune activation.
背景
霉酚酸（MPA）通过抑制肌苷单磷酸脱氢酶（IMPDH）发挥免疫抑制作用。在免疫抑制治疗期间，全血和红细胞样本中已观察到IMPDH活性的诱导。关于IMPDH活性增加机制的信息有限，诱导的潜在影响一直存在争议。
方法
从30例肾移植患者移植前后采集全血、CD4 +细胞和网织红细胞样本。通过实时逆转录聚合酶链反应分析两种IMPDH同工型（1型和2型）的表达，并使用管家基因指数进行定量。通过紫外高效液相色谱法测定IMPDH活性。
结果
移植和免疫抑制治疗的开始与IMPDH1表达增加（50 - 88%，P < 0.0005）和IMPDH2表达降低（42 - 56%，P < 0.0005）相关。然而，在CD4 +细胞中，IMPDH2增加（15%，P = 0.009）。这些变化可能与糖皮质激素的作用有关。移植后两周，接受MPA治疗的患者网织红细胞中IMPDH 1和2升高，表明在长期MPA治疗期间这些细胞中酶被诱导。随访期间发生急性排斥反应的患者移植前CD4 +细胞中IMPDH2表达高于未发生排斥反应的患者（中位表达分别为1.26和0.87，P = 0.017）。
结论
考虑到MPA对IMPDH的作用以及通过测量IMPDH活性对MPA进行药效学监测的可能性，了解移植后和免疫抑制开始后IMPDH 1和2表达的变化很重要。移植前CD4 +细胞中IMPDH2的表达可能是免疫激活的一个指标。
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