Willem Alexander Children's Hospital, Leiden University Medical Center, Leiden, The Netherlands.
Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands.
Blood Adv. 2024 Sep 24;8(18):4767-4777. doi: 10.1182/bloodadvances.2024012945.
Allogeneic hematopoietic stem cell transplantation (HSCT) with mismatched unrelated donors (MMUD) is associated with inferior outcome compared with matched unrelated donors (MUDs). We aimed to identify permissible mismatches using HLA epitope mismatch algorithm, which determines permissibility by analyzing amino acid sequences, in a single-center cohort of 70 pediatric 9/10 MMUD HSCTs and 157 10/10 MUDs for comparison. Amino acid matching was evaluated for the whole HLA protein, the α-helices, and the β-sheets, in both host vs graft (HvG) and graft vs host (GvH) direction. Superior event-free survival (EFS) was found in 13 patients permissibly mismatched in the HvG direction (totalHvG, 92% vs 58% at 1 year; P = .009) and in 21 patients matched on the α-helices (αHvG, 90% vs 53%; P = .002). These rates were similar to EFS rates in patients with 10/10 MUDs (90% vs 80%; P = .60). EFS was not related to β-sheet amino acid matching, nor to matching in the GvH direction. Overall survival (OS) rates trended similarly to those of EFS for amino acid mismatches (totalHvG, 92% vs 74%; P = .075; αHvG, 90% vs 71%; P = .072). These findings were reproduced in an EBMT Registry inborn errors cohort of 271 pediatric 9/10 MMUD HSCTs and 929 10/10 MUD HSCTs, showing a significant effect of αHvG matching on both OS and EFS and similar OS and EFS between αHvG matched MMUDs and 10/10 MUDs. In summary, HvG amino acid matching on the α-helices identifies 9/10 MMUDs with permissible mismatches, which are correlated with favorable transplant outcomes similar to those of matched donors.
异基因造血干细胞移植（HSCT）使用不匹配的无关供体（MMUD）与匹配的无关供体（MUD）相比，结果较差。我们旨在使用 HLA 表位不匹配算法识别允许的不匹配，该算法通过分析氨基酸序列来确定允许性，这是在单中心队列中的 70 例儿科 9/10 MMUD HSCT 和 157 例 10/10 MUD 中进行比较。评估了整个 HLA 蛋白、α-螺旋和β-折叠在宿主与移植物（HvG）和移植物与宿主（GvH）方向上的氨基酸匹配。在 HvG 方向上允许不匹配的 13 例患者（总 HvG，1 年时为 92%比 58%；P=0.009）和在 α-螺旋上匹配的 21 例患者（α HvG，90%比 53%；P=0.002）中发现了更好的无事件生存（EFS）。这些比率与 10/10 MUD 患者的 EFS 比率相似（90%比 80%；P=0.60）。EFS 与β-折叠氨基酸匹配无关，也与 GvH 方向上的匹配无关。对于氨基酸不匹配，总生存（OS）率与 EFS 相似（总 HvG，92%比 74%；P=0.075；α HvG，90%比 71%；P=0.072）。这些发现在 EBMT 登记处的 271 例儿科 9/10 MMUD HSCT 和 929 例 10/10 MUD HSCT 先天错误队列中得到复制，显示出α HvG 匹配对 OS 和 EFS 的显著影响，并且α HvG 匹配的 MMUD 和 10/10 MUD 之间的 OS 和 EFS 相似。总之，α-螺旋上 HvG 的氨基酸匹配确定了具有允许性不匹配的 9/10 MMUD，这与类似于匹配供体的良好移植结果相关。
