Department of Surgery, University of Cambridge, Cambridge, United Kingdom.
Department of Paediatric Nephrology, Nottingham University Hospital, Nottingham, United Kingdom.
Front Immunol. 2023 Mar 15;14:1092335. doi: 10.3389/fimmu.2023.1092335. eCollection 2023.
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 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.
排斥反应仍然是小儿肾移植同种异体移植物失败的主要原因，其由供体-受者 HLA 错配驱动。现代计算算法能够在分子水平上评估 HLA 错配的免疫原性（分子错配，molMM）。虽然已经证明 molMM 与同种免疫结果相关，但缺乏证据表明其对传统抗原错配（antMM）的预测性能有所提高。
我们分析了来自 CERTAIN 注册中心的 177 名患者（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（EMS3D）和 netMHCIIpan（netMHC1k：肽结合亲和力≤1000 nM；netMHC：结合亲和力≤500 nM 且排名<2%）。我们根据 DSA 发展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 基因座中评分最高的 molMM 供体抗原。molMM 评分在预测所有 HLA 基因座的 DSA 方面优于 antMM；EMS3D 算法具有特别一致的性能（所有 HLA 基因座的接收者操作特征曲线下面积（AUC）>0.7，而 antMM 为 0.52-0.70）。ABMR（而非 TCMR）与 HLA-DQ molMM 评分相关（AAMS、EMS3D 和 netMHC）。HLA-DQ molMM 高危患者的移植肾功能恶化风险增加（基线 eGFR 降低 50%（eGFR50），调整后的 HR：3.5，95%CI 1.6-8.2 高 vs. 低 EMS3D）。使用 EMS3D HLA-DQ 分层对 eGFR50 结局进行多变量建模显示，AUC（EMS3D 与 antMM 在 2 年时：0.81 比 0.77，在 4.5 年时：0.72 比 0.64）的区分度更好，与传统 antMM 相比，更多患者分层为低危组。
分子错配在预测体液同种免疫方面优于抗原错配。分子 HLA-DQ 错配似乎是小儿肾移植中移植物功能恶化的一个重要预后因素。
