University of Southern California and Children's Hospital Los Angeles, Los Angeles, California, USA.
Division of Biostatistics, Data Science Institute, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Clin Transplant. 2024 Nov;38(11):e15478. doi: 10.1111/ctr.15478.
When human leukocyte antigen (HLA)-matched donors are not available for hematopoietic stem cell transplants (HSCT), there are no well-accepted guidelines for ranking 7/8 HLA-matched unrelated donors to achieve optimal transplant outcomes. A novel scoring system for ranking HLA mismatches for these donors was investigated.
High-resolution HLA types were used to determine amino acid mismatches located in the HLA antigen-recognition domain. The location and physicochemical properties of mismatched amino acids were used to assign scores for peptide binding, T-cell receptor docking, and HLA structure/function. The scores were tested using a cohort of 2319 patients with leukemia or myelodysplastic syndrome who received their first unrelated donor transplant using conventional graft-versus-host disease (GVHD) prophylaxis between 2000 and 2014. Donors were 7/8 HLA-matched with a single HLA Class I mismatch. Primary outcomes were overall survival and acute GVHD.
The scores did not significantly (p < 0.01) associate with transplant outcomes, although a Peptide Score = 0 (i.e., no differences in peptide binding; N = 146, 6.3%) appears to have lower transplant-related mortality (TRM) compared to higher scores (p = 0.019). HLA mismatches with Peptide Score = 0 were predominately HLA-C*03:03/03:04 (62%), previously reported to be a permissive mismatch, and a group of 28 other HLA mismatches (38%) that showed similar associations with TRM.
This study suggests that HLA mismatches that do not alter peptide binding or orientation (Peptide Score = 0) could expand the number of permissive HLA mismatches. Further investigation is needed to confirm this observation and to explore alternative scoring systems for ranking HLA mismatched donors.
当无法获得人类白细胞抗原 (HLA) 匹配的供体进行造血干细胞移植 (HSCT) 时，对于如何对 7/8 HLA 匹配的无关供体进行排序以实现最佳移植效果，目前尚无被广泛认可的指南。本研究旨在调查一种用于对这些供体进行 HLA 错配排序的新型评分系统。
使用高分辨率 HLA 类型来确定位于 HLA 抗原识别域的氨基酸错配。错配氨基酸的位置和物理化学特性用于分配肽结合、T 细胞受体对接和 HLA 结构/功能的评分。该评分系统在 2000 年至 2014 年间接受过常规移植物抗宿主病 (GVHD) 预防的 2319 例白血病或骨髓增生异常综合征患者队列中进行了测试。这些患者接受了首次无关供体移植，供体与受者存在单个 HLA Ⅰ类错配，且为 7/8 HLA 匹配。主要终点为总生存率和急性 GVHD。
尽管 Peptide Score = 0（即肽结合无差异，N = 146，6.3%）的患者发生移植相关死亡率 (TRM) 似乎低于评分较高的患者（p = 0.019），但评分与移植结果之间无显著关联（p < 0.01）。Peptide Score = 0 的 HLA 错配主要为 HLA-C*03:03/03:04（62%），此前曾报道其为允许性错配，还有 28 个其他 HLA 错配（38%）也与 TRM 有相似的关联。
本研究表明，不会改变肽结合或取向的 HLA 错配（Peptide Score = 0）可能会增加允许性 HLA 错配的数量。需要进一步研究来证实这一观察结果，并探索用于对 HLA 错配供体进行排序的替代评分系统。
