Brouard Sophie, Mansfield Elaine, Braud Christophe, Li Li, Giral Magali, Hsieh Szu-chuan, Baeten Dominique, Zhang Meixia, Ashton-Chess Joanna, Braudeau Cécile, Hsieh Frank, Dupont Alexandre, Pallier Annaik, Moreau Anne, Louis Stéphanie, Ruiz Catherine, Salvatierra Oscar, Soulillou Jean-Paul, Sarwal Minnie
Institut National de la Santé et de la Recherche Médicale, U643, Centre Hospitalier Universitaire de Nantes, Institut de Transplantation et de Recherche en Transplantation, and Université de Nantes, Faculte de Medicine, F-44000 Nantes, France.
Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15448-53. doi: 10.1073/pnas.0705834104. Epub 2007 Sep 14.
Long-term allograft survival generally requires lifelong immunosuppression (IS). Rarely, recipients display spontaneous "operational tolerance" with stable graft function in the absence of IS. The lack of biological markers of this phenomenon precludes identification of potentially tolerant patients in which IS could be tapered and hinders the development of new tolerance-inducing strategies. The objective of this study was to identify minimally invasive blood biomarkers for operational tolerance and use these biomarkers to determine the frequency of this state in immunosuppressed patients with stable graft function. Blood gene expression profiles from 75 renal-transplant patient cohorts (operational tolerance/acute and chronic rejection/stable graft function on IS) and 16 healthy individuals were analyzed. A subset of samples was used for microarray analysis where three-class comparison of the different groups of patients identified a "tolerant footprint" of 49 genes. These biomarkers were applied for prediction of operational tolerance by microarray and real-time PCR in independent test groups. Thirty-three of 49 genes correctly segregated tolerance and chronic rejection phenotypes with 99% and 86% specificity. The signature is shared with 1 of 12 and 5 of 10 stable patients on triple IS and low-dose steroid monotherapy, respectively. The gene signature suggests a pattern of reduced costimulatory signaling, immune quiescence, apoptosis, and memory T cell responses. This study identifies in the blood of kidney recipients a set of genes associated with operational tolerance that may have utility as a minimally invasive monitoring tool for guiding IS titration. Further validation of this tool for safe IS minimization in prospective clinical trials is warranted.
长期同种异体移植存活通常需要终身免疫抑制（IS）。很少有受者在无免疫抑制的情况下表现出具有稳定移植物功能的自发“操作性耐受”。这种现象缺乏生物学标志物，妨碍了对可能产生耐受的患者的识别，而这些患者的免疫抑制可以逐渐减少，并且阻碍了新的诱导耐受策略的开发。本研究的目的是识别操作性耐受的微创血液生物标志物，并使用这些生物标志物来确定在具有稳定移植物功能的免疫抑制患者中这种状态的频率。分析了来自75个肾移植患者队列（操作性耐受/急性和慢性排斥反应/免疫抑制下的稳定移植物功能）和16名健康个体的血液基因表达谱。一部分样本用于微阵列分析，不同患者组的三类比较确定了一个由49个基因组成的“耐受足迹”。这些生物标志物通过微阵列和实时PCR应用于独立测试组中操作性耐受的预测。49个基因中的33个正确区分了耐受和慢性排斥反应表型，特异性分别为99%和86%。该特征分别与接受三联免疫抑制和低剂量类固醇单一疗法的12名稳定患者中的1名以及10名稳定患者中的5名共有。该基因特征表明共刺激信号减少、免疫静止、细胞凋亡和记忆性T细胞反应的模式。本研究在肾移植受者血液中鉴定出一组与操作性耐受相关的基因，这些基因可能作为指导免疫抑制滴定的微创监测工具。有必要在前瞻性临床试验中进一步验证该工具以安全地最小化免疫抑制。
