Outfoxing Rejection: Urinary FOXP3 mRNA, TCMR, and the Fate of Allografts.
Outfoxing Rejection: Urinary FOXP3 mRNA, TCMR, and the Fate of Allografts.
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DOI：
10.1097/tp.0000000000003479
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发表时间：
2021-08-01
期刊：
影响因子：
6.2
通讯作者：
Menon MC
中科院分区：
文献类型：
--
作者：
Tedla FM;Sanchez Russo L;Menon MC
移植肝活检标本的组织病理学检查仍然是诊断包括急性T细胞介导的排斥反应(TCMR)在内的移植物损伤原因的金标准。同种异体移植针活检由于病理的斑块性质以及观察者间和观察者内的可变性而受到抽样误差的影响。此外，活检的侵袭性不利于连续采样来评估TCMR后的治疗反应。因此，几个研究方向都在寻找新的非侵入性生物标志物，用于诊断排斥反应或预测同种异体移植物的命运。这些包括对血液、组织或尿液中激活的免疫细胞的基因表达谱或细胞产物进行量化。非侵入性排斥诊断领域的翻译进展的例证是在临床上采用外周单个核细胞的基因表达谱用于低危心脏移植的免疫监测，作为监测心内膜心肌活检的替代。1几种检测方法也处于不同的发展阶段，用于肾移植受者的护理。2在这一期的移植中，Luan等人在他们现有的关于尿液细胞mRNA图谱在诊断或预测TCMR4-6可逆性方面的工作中增加了新的内容。他们比较了参与器官移植临床试验-04(CTOT-04)的三组患者的18SRRNA标准化对数转化尿细胞FXP3、CD25、CD3E和穿孔素的水平：发生急性移植物抗宿主病的患者；无排斥反应病理证据的患者(无排斥组)；以及平均血清肌酐≤为2 mg/dL且未接受移植后12个月内急性排斥反应、巨细胞病毒或BK感染治疗的患者(稳定组)。有交界性排斥反应、抗体介导的排斥反应或BK病毒肾病的患者被排除。TCMR组中位数尿中位数高于无排斥或稳定组。在33例TCMR组患者中，可逆性TCMR患者(即21例4周肌酐在基线15%以内的患者)的尿细胞FOXP3mRNA水平(但不包括其他mRNAs)高于不可逆TCMR患者。18S rRNA标准化对数转化的尿细胞FOXP3mRNA为-1.33预测TCMR逆转的敏感性为75%，特异性为67%。有趣的是，前瞻性的尿mRNA轨迹分析显示，TCMR可逆性患者在TCMR治疗后有更高的FOXP3 mRNA和更低的CTOT-4签名评分，而那些不可逆TCMR患者尿中FOXP3 mRNA更低，CTOT-4签名评分更高(CTOT-04签名是尿液18S rRNA、CD3E和先前与TCMR6相关的CD3E和干扰素诱导蛋白10[IP-10]mRNA的组合)。多因素Logistic回归分析显示，尿细胞FOXP3mRNA水平可独立于临床变量预测TCMR逆转。结合临床变量和尿细胞FOXP3 mRNA水平的TCMR可逆性预测模型优于仅有临床变量或FOXP3 mRNA水平的模型。重要的是，FOXP3mRNA水平与死亡审查移植物存活率的改善独立相关，作者报告称，在他们调整的分析中，这种关联是通过TCMR可逆性介导的。Luan等人的发现在一个独立的多中心前瞻性队列中优雅地验证了他们之前关于FOXP3mRNA和TCMR可逆性之间的关联的报告。这些发现可能在调整…的抗中药治疗强度方面具有重要的临床实用价值。
Histopathologic examination of allograft biopsy specimens remains the gold standard to diagnose the causes of allograft injury including acute T cell–mediated rejection (TCMR). Allograft needle biopsies suffer from sampling errors from patchy nature of pathology, as well as inter-and intraobserver variability. Additionally, the invasive nature of biopsies discourages serial sampling to assess response to therapy after TCMR. Several lines of research have thus pursued novel noninvasive biomarkers for diagnosis of rejection or prognostication of allograft fate. These have involved quantitation of gene expression profiles or cellular products of activated immune cells in blood, tissue, or urine. Translational progress in the field of noninvasive rejection diagnostics is exemplified by the adoption in clinic of gene expression profiling of peripheral mononuclear cells for immune surveillance of low-risk heart transplants as a substitute for surveillance endomyocardial biopsies. 1 Several assays are also in various stages of development for use in the care of kidney transplant recipients. 2 In this issue of Transplantation, Luan et al3 add to their existing body of work on the utility of urinary cell mRNA profiling in diagnosing or predicting the reversibility of TCMR4-6. They compared 18s rRNA-normalized logtransformed urinary cell mRNA levels of FOXP3, CD25, CD3E, and perforin in 3 subgroups of patients who participated in the Clinical Trials in Organ Transplantation-04 (CTOT-04): patients who developed acute TCMR; patients who had no pathologic evidence of TCMR (No Rejection group); and patients with average serum creatinine≤ 2 mg/dL who had not undergone allograft biopsy and not required treatment for acute rejection, or cytomegaloviral or BK infection within 12 months of transplant (Stable group). Patients with borderline rejection, antibody-mediated rejection, or BK virus nephropathy were excluded. Median urinary levels of all mRNAs were higher in the TCMR group than the No Rejection or Stable groups. Among 33 patients in the TCMR group, median urinary cell FOXP3 mRNA level (but not other mRNAs) was higher in those with reversible TCMR (ie, 21 patients with 4-week creatinine within 15% of baseline) than in nonreversible TCMR. An 18s rRNA-normalized log-transformed urinary cell FOXP3 mRNA of–1.33 predicted TCMR reversal with a sensitivity of 75% and specificity of 67%. Interestingly, prospective urinary mRNA trajectory analyses showed that patients with TCMR-reversibility had higher FOXP3 mRNA but a lower CTOT-4 signature score after TCMR treatment, whereas those with nonreversible TCMR had lower urinary FOXP3 mRNA and higher CTOT-4 signature scores (CTOT-04 signature is a composite of urinary 18s rRNA, and CD3E and interferon-inducible protein 10 [IP-10] mRNA previously associated with TCMR6). Multiple logistic regression showed urinary cell FOXP3 mRNA level predicted TCMR reversal independent of clinical variables. A predictive model for TCMR-reversibility that combined clinical variables and urinary cell FOXP3 mRNA level outperformed a model with clinical variables or FOXP3 mRNA alone. Importantly, FOXP3 mRNA levels were independently associated with improved death-censored graft survival, an association that the authors reported to be mediated through TCMR-reversibility in their adjusted analyses. The findings by Luan et al elegantly validate in an independent multicenter prospective cohort their previous report of the association between FOXP3 mRNA and TCMR-reversibility. 5 These findings could have significant potential clinical utility in tailoring the intensity of anti-TCMR therapy …