首个包含免疫抑制药物治疗调整的肾移植术后免疫耐受的共识基因表达特征的建立和验证。
Development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy.
机构信息
MRC Centre for Transplantation, King's College London, Great Maze Pond, London SE1 9RT, UK; Biostatistics and Health Informatics Department, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespigny Park, London SE5 8AF, UK.
NIHR Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, Great Maze Pond, London SE1 9RT, UK.
出版信息
EBioMedicine. 2020 Aug;58:102899. doi: 10.1016/j.ebiom.2020.102899. Epub 2020 Jul 21.
BACKGROUND
Kidney transplant recipients (KTRs) with "operational tolerance" (OT) maintain a functioning graft without immunosuppressive (IS) drugs, thus avoiding treatment complications. Nevertheless, IS drugs can influence gene-expression signatures aiming to identify OT among treated KTRs.
METHODS
We compared five published signatures of OT in peripheral blood samples from 18 tolerant, 183 stable, and 34 chronic rejector KTRs, using gene-expression levels with and without adjustment for IS drugs and regularised logistic regression.
FINDINGS
IS drugs explained up to 50% of the variability in gene-expression and 20-30% of the variability in the probability of OT predicted by signatures without drug adjustment. We present a parsimonious consensus gene-set to identify OT, derived from joint analysis of IS-drug-adjusted expression of five published signature gene-sets. This signature, including CD40, CTLA4, HSD11B1, IGKV4-1, MZB1, NR3C2, and RAB40C genes, showed an area under the curve 0⋅92 (95% confidence interval 0⋅88-0⋅94) in cross-validation and 0⋅97 (0⋅93-1⋅00) in six months follow-up samples.
INTERPRETATION
We advocate including adjustment for IS drug therapy in the development stage of gene-expression signatures of OT to reduce the risk of capturing features of treatment, which could be lost following IS drug minimisation or withdrawal. Our signature, however, would require further validation in an independent dataset and a biomarker-led trial.
FUNDING
FP7-HEALTH-2012-INNOVATION-1 [305147:BIO-DrIM] (SC,IR-M,PM,DSt); MRC [G0801537/ID:88245] (MPH-F); MRC [MR/J006742/1] (IR-M); Guy's&StThomas' Charity [R080530]&[R090782]; CONICYT-Bicentennial-Becas-Chile (EN-L); EU:FP7/2007-2013 [HEALTH-F5-2010-260687: The ONE Study] (MPH-F); Czech Ministry of Health [NV19-06-00031] (OV); NIHR-BRC Guy's&StThomas' NHS Foundation Trust and KCL (SC); UK Clinical Research Networks [portfolio:7521].
背景
具有“操作性耐受”（OT）的肾移植受者（KTR）在不使用免疫抑制（IS）药物的情况下维持功能移植物，从而避免治疗并发症。然而，IS 药物可以影响基因表达特征，以在接受治疗的 KTR 中识别 OT。
方法
我们比较了 18 名耐受、183 名稳定和 34 名慢性排斥 KTR 外周血样本中的五个已发表的 OT 特征，使用基因表达水平和不调整 IS 药物和正则化逻辑回归调整 IS 药物。
结果
IS 药物解释了基因表达和未调整药物的 OT 预测概率的 20-30%的变异的 50%。我们提出了一个简洁的共识基因集，用于识别 OT，该基因集源自五个已发表的特征基因集的 IS 药物调整后表达的联合分析。该特征包括 CD40、CTLA4、HSD11B1、IGKV4-1、MZB1、NR3C2 和 RAB40C 基因，在交叉验证中曲线下面积为 0.92（95%置信区间为 0.88-0.94），在六个月随访样本中为 0.97（0.93-1.00）。
解释
我们主张在 OT 的基因表达特征的开发阶段纳入 IS 药物治疗的调整，以降低捕获治疗特征的风险，这些特征在 IS 药物最小化或停药后可能会丢失。然而，我们的特征需要在独立数据集和基于生物标志物的试验中进一步验证。
资金
FP7-HEALTH-2012-INNOVATION-1 [305147：BIO-DrIM]（SC、IR-M、PM、DSt）；MRC [G0801537/ID：88245]（MPH-F）；MRC [MR/J006742/1]（IR-M）；盖伊与圣托马斯慈善基金会[R080530]&[R090782]；CONICYT-Bicentennial-Becas-Chile（EN-L）；欧盟：FP7/2007-2013 [HEALTH-F5-2010-260687：The ONE 研究]（MPH-F）；捷克卫生部[NV19-06-00031]（OV）；NIHR-BRC 盖伊与圣托马斯 NHS 基金会信托基金和 KCL（SC）；英国临床研究网络[投资组合：7521]。
Zotero 插件