FOXP3 mRNA Profile Prognostic of Acute T Cell-mediated Rejection and Human Kidney Allograft Survival.
FOXP3 mRNA Profile Prognostic of Acute T Cell-mediated Rejection and Human Kidney Allograft Survival.
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DOI：
10.1097/tp.0000000000003478
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发表时间：
2021-08-01
期刊：
影响因子：
6.2
通讯作者：
Suthanthiran M
中科院分区：
文献类型：
--
作者：
Luan D;Dadhania DM;Ding R;Muthukumar T;Lubetzky M;Lee JR;Sharma VK;August P;Mueller FB;Schwartz JE;Suthanthiran M
t细胞介导的排斥反应（TCMR）是最常见的急性排斥反应类型，与同种异体肾移植衰竭有关。几乎40%的TCMR发作对治疗无反应，无反应的分子机制尚不清楚。我们的单中心研究发现尿细胞FOXP3 mRNA丰度预测TCMR可逆性和同种异体移植存活。我们开发了PCR检测方法，并测量了来自480名异体肾移植受者的3559份尿液中FOXP3、CD25、CD3E、穿孔素和18S rRNA转录本的绝对拷贝数，这些尿被前瞻性地纳入了器官移植多中心临床试验-04。在这项重复性研究中，我们研究了mRNA谱与TCMR诊断、TCMR可逆性和同种异体移植物存活之间的关系。FOXP3 （P=0.01， Kruskal-Wallis检验）、CD25 （P=0.01）、CD3E （P<0.0001）、perforin (P<0.0001) mRNA的18S rRNA归一化水平是TCMR的诊断指标，但只有FOXP3 mRNA水平能预测TCMR的可逆性（ROC AUC=0.764； 95%可信区间为0.611 ~ 0.917；P=0.008）。多变量logistic回归分析显示，尿细胞FOXP3 mRNA水平预测逆转，与临床变量无关。临床变量与FOXP3 mRNA的复合模型（AUC = 0.889, 95% CI 0.781 ~ 0.997， P<0.001）在预测TCMR可逆性方面优于FOXP3 mRNA或临床变量（P=0.01，似然比检验）。多变量Cox比例风险回归分析显示，FOXP3 mRNA水平预测同种异体肾移植存活（P=0.047），但在控制TCMR逆转后（P=0.477）不能预测同种异体肾移植存活。尿细胞FOXP3 mRNA水平可诊断TCMR，预测TCMR可逆性，并通过TCMR逆转机制预测异体肾移植存活。
T-cell–mediated rejection (TCMR) is the most frequent type of acute rejection and is associated with kidney allograft failure. Almost 40% of TCMR episodes are nonresponsive to therapy and molecular mechanisms for the nonresponsiveness are unknown. Our single-center study identified that urinary cell FOXP3 mRNA abundance predicts TCMR reversibility and allograft survival. We developed PCR assays and measured absolute copy numbers of transcripts for FOXP3, CD25, CD3E, perforin, and 18S rRNA in 3559 urines from 480 kidney allograft recipients prospectively enrolled in the multicenter Clinical Trials in Organ Transplantation-04. In this replication study, we investigated the association between mRNA profile and TCMR diagnosis, TCMR reversibility and allograft survival. 18S rRNA normalized levels of mRNA for FOXP3 (P=0.01, Kruskal-Wallis test), CD25 (P=0.01), CD3E (P<0.0001), and perforin (P<0.0001) were diagnostic of TCMR, but only FOXP3 mRNA level predicted TCMR reversibility (ROC AUC=0.764; 95% confidence interval, 0.611 to 0.917; P=0.008). Multivariable logistic regression analyses showed that urinary cell FOXP3 mRNA level predicted reversal, independent of clinical variables. A composite model of clinical variables and FOXP3 mRNA (AUC = 0.889; 95% CI, 0.781 to 0.997; P<0.001) outperformed FOXP3 mRNA or clinical variables in predicting TCMR reversibility (P=0.01, likelihood ratio test). Multivariable Cox proportional hazards regression analyses showed that FOXP3 mRNA level predicts kidney allograft survival (P=0.047), but not after controlling for TCMR reversal (P=0.477). Urinary cell level of FOXP3 mRNA is diagnostic of TCMR, predicts TCMR reversibility, and is prognostic of kidney allograft survival via a mechanism involving TCMR reversal.