Molecular HLA mismatching for prediction of primary humoral alloimmunity and graft function deterioration in paediatric kidney transplantation.
Molecular HLA mismatching for prediction of primary humoral alloimmunity and graft function deterioration in paediatric kidney transplantation.
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DOI：
10.3389/fimmu.2023.1092335
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发表时间：
2023
影响因子：
7.3
通讯作者：
Kosmoliaptsis, Vasilis
中科院分区：
文献类型：
--
作者：
Kim, Jon Jin;Fichtner, Alexander;Copley, Hannah C.;Gragert, Loren;Suesal, Caner;Dello Strologo, Luca;Oh, Jun;Pape, Lars;Weber, Lutz T.;Weitz, Marcus;Koenig, Jens;Krupka, Kai;Toenshoff, Burkhard;Kosmoliaptsis, Vasilis
关键词：
排斥反应仍然是小儿肾移植中同种异体移植物失败的主要原因，并且是由供体-受体HLA错配驱动的。现代计算算法能够在分子水平上评估HLA错配免疫原性（分子错配，molMM）。虽然molMM已被证明与同种免疫结果相关，但缺乏证据证明对传统抗原错配（antMM）的预测性能有所改善。我们分析了来自CERTAIN登记研究的177例患者（中位随访时间为4.5年）。molMM评分包括氨基酸错配评分（AAMS）、静电错配评分（EMS 3D）和netMHCIIpan（netMHC 1 k：肽结合亲和力≤1000 nM; netMHC：结合亲和力≤500 nM加上秩<2%）。我们根据DSA发展的风险模型将患者分为高/低风险组。供体特异性HLA抗体（DSA）主要靶向每个HLA基因座内评分最高的molMM供体抗原。MolMM评分在预测所有HLA基因座的新发DSA方面提供了优于antMM的上级区分度; EMS 3D算法具有特别一致的性能（所有HLA基因座的受试者工作特征曲线下面积（AUC）>0.7，而antMM为0.52-0.70）。ABMR（而非TCMR）与HLA-DQ molMM评分（AAMS、EMS 3D和netMHC）相关。高风险HLA-DQ molMM患者的移植物功能恶化风险增加（基线eGFR（eGFR 50）降低50%，校正HR：3.5，95% CI 1.6-8.2高vs.低EMS 3D）。使用EMS 3D HLA-DQ分层对eGFR 50结局进行多变量建模，显示出更好的区分度（AUC EMS 3D vs. antMM，2年：0.81 vs. 0.77，4.5年：0.72 vs. 0.64），与传统antMM相比，将更多患者分层为低风险组。在预测体液同种免疫方面，分子错配比抗原错配优越上级。分子HLA-DQ错配似乎是小儿肾移植术后移植肾功能恶化的一个重要预后因素。
Rejection remains the main cause of allograft failure in paediatric kidney transplantation and is driven by donor-recipient HLA mismatching. Modern computational algorithms enable assessment of HLA mismatch immunogenicity at the molecular level (molecular-mismatch, molMM). Whilst molMM has been shown to correlate with alloimmune outcomes, evidence demonstrating improved prediction performance against traditional antigen mismatching (antMM) is lacking. We analysed 177 patients from the CERTAIN registry (median follow-up 4.5 years). molMM scores included Amino-Acid-Mismatch-Score (AAMS), Electrostatic-Mismatch-Score (EMS3D) and netMHCIIpan (netMHC1k: peptide binding affinity ≤1000 nM; netMHC: binding affinity ≤500 nM plus rank <2%). We stratified patients into high/low-risk groups based on risk models of DSA development. Donor-specific HLA antibodies (DSA) predominantly targeted the highest scoring molMM donor antigen within each HLA locus. MolMM scores offered superior discrimination versus antMM in predicting de novo DSA for all HLA loci; the EMS3D algorithm had particularly consistent performance (area under the receiver operating characteristic curve (AUC) >0.7 for all HLA loci vs. 0.52-0.70 for antMM). ABMR (but not TCMR) was associated with HLA-DQ molMM scores (AAMS, EMS3D and netMHC). Patients with high-risk HLA-DQ molMM had increased risk of graft function deterioration (50% reduction in baseline eGFR (eGFR50), adjusted HR: 3.5, 95% CI 1.6-8.2 high vs. low EMS3D). Multivariable modelling of the eGFR50 outcome using EMS3D HLA-DQ stratification showed better discrimination (AUC EMS3D vs. antMM at 2 years: 0.81 vs. 0.77, at 4.5 years: 0.72 vs. 0.64) and stratified more patients into the low-risk group, compared to traditional antMM. Molecular mismatching was superior to antigen mismatching in predicting humoral alloimmunity. Molecular HLA-DQ mismatching appears to be a significant prognostic factor for graft function deterioration in paediatric kidney transplantation.
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影响因子：
7.3
作者：
Copley HC;Gragert L;Leach AR;Kosmoliaptsis V
通讯作者：
Kosmoliaptsis V
DOI：
10.2215/cjn.10860917
发表时间：
2018-05-07
影响因子：
9.8
作者：
Leeaphorn, Napat;Pena, Jeremy Ryan A.;Cardarelli, Francesca
通讯作者：
Cardarelli, Francesca
影响因子：
4.4
作者：
Mallon, Dermot H.;Kling, Christiane;Kosmoliaptsis, Vasilis
通讯作者：
Kosmoliaptsis, Vasilis
影响因子：
19.6
作者：
Kosmoliaptsis, Vasilios;Gjorgjimajkoska, Olivera;Bradley, J. Andrew
通讯作者：
Bradley, J. Andrew
DOI：
10.1007/s00467-021-05078-9
发表时间：
2021-12
期刊：
Pediatric nephrology (Berlin, Germany)
影响因子：
--
作者：
Charnaya O;Jones J;Philogene MC;Chiang PY;Segev DL;Massie AB;Garonzik-Wang J
通讯作者：
Garonzik-Wang J