Comparative Transcriptional and Phenotypic Peripheral Blood Analysis of Kidney Recipients Under Cyclosporin A or Sirolimus Monotherapy
Comparative Transcriptional and Phenotypic Peripheral Blood Analysis of Kidney Recipients Under Cyclosporin A or Sirolimus Monotherapy
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DOI：
10.1111/j.1600-6143.2010.03302.x
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发表时间：
2010-12-01
影响因子：
8.8
通讯作者：
Sanchez-Fueyo, A.
中科院分区：
文献类型：
--
作者：
Brouard, S.;Puig-Pey, I.;Sanchez-Fueyo, A.
由于其低水平的肾毒性和利用致耐受性途径的能力，西罗莫司（SRL）已被提议作为移植中钙调磷酸酶抑制剂的替代品。然而，其在人类中独特的免疫抑制作用的确切机制仍不清楚。在目前的研究中，我们的目的是描述在体内的影响，SRL相比，环孢素A（CSA），采用基因表达谱和多参数流式细胞术对血细胞收集稳定的肾受体下免疫抑制剂单药治疗。SRL受体显示出增加的CD4 + CD25highFoxp3 + T细胞频率。然而，这伴随着效应记忆T细胞数量的增加以及NF κ B相关促炎表达途径和单核细胞和NK细胞谱系特异性转录物的富集。此外，测量的转录签名特征的操作耐受肾受体未能检测SRL和CSA治疗的收件人之间的差异。总之，我们在这里表明，在体内由SRL单一疗法诱导的血液转录谱不类似于操作耐受受体，并且由先天免疫细胞和NF κ B相关的促炎事件主导。这些数据为临床移植中SLR对免疫系统的复杂影响提供了新的见解。
Due to its low level of nephrotoxicity and capacity to harness tolerogenic pathways, sirolimus (SRL) has been proposed as an alternative to calcineurin inhibitors in transplantation. The exact mechanisms underlying its unique immunosuppressive profile in humans, however, are still not well understood. In the current study, we aimed to depict the in vivo effects of SRL in comparison with cyclosporin A (CSA) by employing gene expression profiling and multiparameter flow cytometry on blood cells collected from stable kidney recipients under immunosuppressant monotherapy. SRL recipients displayed an increased frequency of CD4 + CD25highFoxp3 + T cells. However, this was accompanied by an increased number of effector memory T cells and by enrichment in NFkB-related pro-inflammatory expression pathways and monocyte and NK cell lineage-specific transcripts. Furthermore, measurement of a transcriptional signature characteristic of operationally tolerant kidney recipients failed to detect differences between SRL and CSA-treated recipients. In conclusion, we show here that the blood transcriptional profile induced by SRL monotherapy in vivo does not resemble that of operationally tolerant recipients and is dominated by innate immune cells and NFkB-related pro-inflammatory events. These data provide novel insights on the complex effects of SLR on the immune system in clinical transplantation.