Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling
Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling
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DOI：
10.1111/j.1600-6143.2005.01175.x
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发表时间：
2006-01-01
影响因子：
8.8
通讯作者：
Hunt, S
中科院分区：
文献类型：
--
作者：
Deng, MC;Eisen, HJ;Hunt, S
通过肌内膜活检（EMB）诊断排斥是侵入性的，昂贵的和可变的。我们研究了外周血单核细胞（PBMC）的基因表达谱以区分ISHLT 0级排斥（静止期）和中度/重度排斥（ISHLT >= 3A）。在移植后访视时前瞻性随访患者并采集血样。活检组织由当地的ISHLT标准和三名对临床数据不知情的独立病理学家进行分级。已知的同种免疫途径和白细胞微阵列确定了252个候选基因，并开发了实时PCR检测。使用线性判别分析（LDA）从训练集（n = 145个样品，107名患者）获得11个基因的实时PCR测试，转换成评分（0-40），并在独立集（n = 63个样品，63名患者）中进行前瞻性验证。在验证集中，该检验区分了活检定义的中度/重度排斥和静止（p = 0.0018），与ISHLT ≥ 3A级排斥的一致性为84%（95%CI 66%C94%）。移植后> 1年且评分低于30分的患者（约占研究人群的68%）极不可能发生≥ 3A级排斥反应（NPV = 99.6%）。基因表达检测可以检测出不存在中度/重度排斥反应，从而避免在某些临床环境中进行活检。需要更多的临床经验来确定分子检测在临床事件预测和免疫抑制管理中的作用。
Rejection diagnosis by endomyocardial biopsy (EMB) is invasive, expensive and variable. We investigated gene expression profiling of peripheral blood mononuclear cells (PBMC) to discriminate ISHLT grade 0 rejection (quiescence) from moderate/severe rejection (ISHLT >= 3A). Patients were followed prospectively with blood sampling at post-transplant visits. Biopsies were graded by ISHLT criteria locally and by three independent pathologists blinded to clinical data. Known alloimmune pathways and leukocyte microarrays identified 252 candidate genes for which real-time PCR assays were developed. An 11 gene realtime PCR test was derived from a training set (n = 145 samples, 107 patients) using linear discriminant analysis (LDA), converted into a score (0-40), and validated prospectively in an independent set (n = 63 samples, 63 patients). The test distinguished biopsydefined moderate/severe rejection from quiescence (p = 0.0018) in the validation set, and had agreement of 84% (95% CI 66% C94%) with grade ISHLT >= 3A rejection. Patients > 1 year post-transplant with scores below 30 (approximately 68% of the study population) are very unlikely to have grade >= 3A rejection (NPV = 99.6%). Gene expression testing can detect absence of moderate/severe rejection, thus avoiding biopsy in certain clinical settings. Additional clinical experience is needed to establish the role of molecular testing for clinical event prediction and immunosuppression management.