Predicting Cellular Rejection With a Cell-Based Assay: Preclinical Evaluation in Children.
Predicting Cellular Rejection With a Cell-Based Assay: Preclinical Evaluation in Children.
复制标题
DOI：
10.1097/tp.0000000000001076
复制
发表时间：
2017-01
期刊：
影响因子：
6.2
通讯作者：
Sindhi R
中科院分区：
文献类型：
--
作者：
Ashokkumar C;Soltys K;Mazariegos G;Bond G;Higgs BW;Ningappa M;Sun Q;Brown A;White J;Levy S;Fazzolare T;Remaley L;Dirling K;Harris P;Hartle T;Kachmar P;Nicely M;OʼToole L;Boehm B;Jativa N;Stanley P;Jaffe R;Ranganathan S;Zeevi A;Sindhi R
同种特异性CD154+ T细胞毒性记忆细胞（CD154+TcM）可预测小队列儿童肝或肠移植（LTx，ITx）后的急性细胞排斥反应（ACR），并可增强免疫抑制治疗，但有待验证和临床实施。为了确定安全性和可能的益处，在来自214名<21岁的儿童（NCT#1163578）的冷冻保存样品中测量了CD154+TcM。在试验标准化和重现性试验后，使用研究级试剂检测了训练集样本（n=158），并使用cGMP生产的试剂检测了122份独立验证集样本。在平行培养中，由供体细胞刺激诱导的CD154+TcM表达为由HLA不相同细胞诱导的CD154+TcM的分数。所得免疫反应性指数（IR）如果> 1则意味着排斥风险增加。训练集和验证集受试者在人口统计学上相似。在几种条件下，平均测试变异系数<10%。结合几个混杂变量的逻辑回归确定了用于预测相应训练集样本中的排斥反应的单独的移植前和移植后IR阈值。移植后训练样本中IR ≥ 1.1和移植前训练样本中IR ≥1.23预测相应验证集样本在60天后采样期的LTx或ITx排斥反应，灵敏度、特异性、阳性和阴性预测值分别为84%、80%、64%和92（AUC 0.792）和57%、89%、78%和74%（AUC 0.848）。静脉切开术未发生不良事件。同种异体特异性CD154+ T细胞毒性记忆细胞预测儿童肝或肠移植后急性细胞排斥反应辅助使用可增强临床结局。
Allospecific CD154+T-cytotoxic memory cells (CD154+TcM) predict acute cellular rejection (ACR) after liver or intestine transplantation (LTx, ITx) in small cohorts of children and can enhance immunosuppression management, but await validation and clinical implementation. To establish safety and probable benefit, CD154+TcM were measured in cryopreserved samples from 214 children <21 years (NCT#1163578). Training set samples, n=158, were tested with research-grade reagents and 122 independent validation set samples were tested with cGMP-manufactured reagents after assay standardization and reproducibility testing. Recipient CD154+TcM induced by stimulation with donor cells were expressed as a fraction of those induced by HLA-non-identical cells in parallel cultures. The resulting immunoreactivity index (IR) if > 1 implies increased rejection-risk. Training and validation set subjects were demographically similar. Mean coefficient of test variation was <10% under several conditions. Logistic regression incorporating several confounding variables identified separate pre-transplant and post-transplant IR thresholds for prediction of rejection in respective training set samples. An IR ≥ 1.1 in post-transplant training samples, and IR ≥1.23 in pre-transplant training samples predicted LTx or ITx rejection in corresponding validation set samples in the 60-day post-sampling period with sensitivity, specificity, positive and negative predictive values of 84%, 80%, 64%, and 92%, respectively (AUC 0.792), and 57%, 89%, 78%, and 74%, respectively (AUC 0.848). No adverse events were encountered due to phlebotomy. Allospecific CD154+T-cytotoxic memory cells predict acute cellular rejection after liver or intestine transplantation in children. Adjunctive use can enhance clinical outcomes.