Demir Zeynep, Raynaud Marc, Divard Gillian, Louis Kevin, Truchot Agathe, Niemann Matthias, Ponsirenas Renata, Aubert Olivier, Del Bello Arnaud, Hertig Alexandre, Anglicheau Dany, Dale Bethany, Kamar Nassim, Mangiola Massimo, Zeevi Adriana, Lefaucheur Carmen, Loupy Alexandre
Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration, Paris, France.
Department of Nephrology and Kidney Transplantation, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
Nat Commun. 2025 Jul 1;16(1):5692. doi: 10.1038/s41467-025-60485-y.
Several in-silico methods emerge to assess HLA immunogenicity and stratify immunological risk, including HLA molecular mismatches and HLA evolutionary divergence (HED). However, their added value in risk-stratifying antibody-mediated rejection (AMR) remains uncertain. We include 5159 kidney transplant recipients from four centers. Thirty-three clinical and immunological parameters are assessed, including HLA eplet mismatches, PIRCHE-II scores, and HED. Their associations with AMR are evaluated using Cox models. AMR occurrs in 1024 patients (19.9%). Immunological determinants of AMR include anti-HLA DSA (MFI:500-1400, HR:1.87; MFI > 1400, HR:3.84, p < 0.001) and HLA Class II eplet mismatches (HR:1.02, p < 0.001). HLA-DQB1-derived (HR:1.01, p = 0.005) and HLA-DRB1-derived PIRCHE-II scores (HR:1.01, p = 0.001) are also associated with AMR, while HED is not. These findings remain consistent across centers and subpopulations, including non-sensitized patients (n = 4137). Our findings show that Class II molecular mismatches are independently associated with AMR. HED shows no association, suggesting limited utility for immune-risk stratification at a population level. Clinicaltrials.gov: NCT06436586.
出现了几种计算机模拟方法来评估HLA免疫原性并分层免疫风险，包括HLA分子错配和HLA进化差异（HED）。然而，它们在分层抗体介导的排斥反应（AMR）风险方面的附加价值仍不确定。我们纳入了来自四个中心的5159名肾移植受者。评估了33项临床和免疫参数，包括HLA表位错配、PIRCHE-II评分和HED。使用Cox模型评估它们与AMR的关联。1024名患者（19.9%）发生了AMR。AMR的免疫决定因素包括抗HLA DSA（MFI：500 - 1400，HR：1.87；MFI > 1400，HR：3.84，p < 0.001）和HLA II类表位错配（HR：1.02，p < 0.001）。HLA - DQB1衍生的（HR：1.01，p = 0.005）和HLA - DRB1衍生的PIRCHE-II评分（HR：1.01，p = 0.001）也与AMR相关，而HED则不然。这些发现跨中心和亚组人群保持一致，包括未致敏患者（n = 4137）。我们的研究结果表明，II类分子错配与AMR独立相关。HED未显示出相关性，表明在人群水平上免疫风险分层的效用有限。Clinicaltrials.gov：NCT06436586。
