Division of Nephrology, Department of Pediatrics, Stanford University, Palo Alto, CA, USA.
Am J Transplant. 2012 May;12(5):1218-28. doi: 10.1111/j.1600-6143.2011.03928.x. Epub 2012 Feb 2.
To identify biomarkers of operational tolerance in pediatric and adult liver transplant recipients, transcriptional profiles were examined from 300 samples by microarrays and Q-PCR measurements of blood specimens from pediatric and adult liver transplant recipients and normal tissues. Tolerance-specific genes were validated in independent samples across two different transplant programs and validated by Q-PCR. A minimal set of 13 unique genes, highly expressed in natural killer cells (p = 0.03), were significantly expressed in both pediatric and adult liver tolerance, irrespective of different clinical and demographic confounders. The performance of this gene set by microarray in independent samples was 100% sensitivity and 83% specificity and the AUC was 0.988 for only three genes by Q-PCR. 26% of adults and 64% of children with excellent liver allograft function, on minimal or dual immunosuppression, showed high prediction scores for tolerance. Novel peripheral transcriptional profiles can be identified in operational tolerance in pediatric and adult recipients of liver allografts, suggesting a high incidence of a pro-tolerogenic phenotype in stable patients on chronic immunosuppression. Given the high incidence of viral infections and malignancies in liver transplant recipients, this gene set provides an important monitoring tool that can move the field toward personalized and predictive medicine in organ transplantation.
为了鉴定小儿和成人肝移植受者免疫耐受的生物标志物，我们通过微阵列和小儿及成人肝移植受者血标本的 Q-PCR 测量，分析了 300 个样本的转录谱。在两个不同的移植项目中，通过 Q-PCR 验证了在独立样本中耐受特异性基因的验证。一组由 13 个独特的基因组成，在自然杀伤细胞中高表达（p = 0.03），在小儿和成人肝耐受中均有显著表达，而不受不同的临床和人口统计学混杂因素的影响。该基因集在独立样本中的微阵列性能为 100%的敏感性和 83%的特异性，而 Q-PCR 仅用三个基因的 AUC 为 0.988。在最小或双重免疫抑制下，具有优异肝移植物功能的成人和儿童中，26%和 64%显示出对耐受的高预测评分。在稳定接受慢性免疫抑制的患者中，可识别新的外周转录谱，提示在慢性免疫抑制患者中存在高发生率的耐受前表型。鉴于肝移植受者中病毒感染和恶性肿瘤的高发生率，该基因集提供了一个重要的监测工具，可以使器官移植领域朝着个性化和预测性医学发展。
