BACKGROUND The success of unrelated haemopoietic cell transplantation (HCT) is limited by graft-versus-host disease (GVHD), which is the main post-transplantation challenge when HLA-matched donors are unavailable. A sequence dimorphism in exon 1 of HLA-B gives rise to leader peptides containing methionine (Met; M) or threonine (Thr; T), which differentially influence natural killer and T-cell alloresponses. The main aim of the study was to evaluate the role of the leader dimorphism in GVHD after HLA-B-mismatched unrelated HCT. METHODS We did a retrospective cohort study of 33 982 patients who received an unrelated HCT done in Australia, Europe, Japan, North America, and the UK between Jan 1, 1988, and Dec 31, 2016. Data were contributed by participants of the International Histocompatibility Working Group in Hematopoietic Cell Transplantation. All cases were included and there were no exclusion criteria. Multivariate regression models were used to assess risks associated with HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 mismatching. Among the 33 982 transplantations, the risks of GVHD associated with HLA-B M and T leaders were established in 17 100 (50·3%) HLA-matched and 1457 (4·3%) single HLA-B-mismatched transplantations using multivariate regression models. Leader frequencies were defined in 2 004 742 BeTheMatch US registry donors. FINDINGS Between Jan 20, 2017, and March 11, 2019, we assessed 33 982 HCTs using multivariate regression models for the role of HLA mismatching on outcome. Median follow-up was 1841 days (IQR 909-2963). Mortality and GVHD increased with increasing numbers of HLA mismatches. A single HLA-B mismatch increased grade 3-4 acute GVHD (odds ratio [OR] 1·89, 95% CI 1·53-2·33; p<0·0001). Among the single HLA-B-mismatched transplantations, acute GVHD risk was higher with leader mismatching than with leader matching (OR 1·73, 1·02-2·94; p=0·042 for grade 2-4) and with an M leader shared allotype compared with a T leader shared allotype (OR 1·98, 1·39-2·81; p=0·0001 for grade 3-4). The preferred HLA-B-mismatched donor is leader-matched and shares a T leader allotype. The majority (1 836 939 [91·6%]) of the 2 004 742 US registry donors have the TT or MT genotype. INTERPRETATION The HLA-B leader informs GVHD risk after HLA-B-mismatched unrelated HCT and differentiates high-risk HLA-B mismatches from those with lower risk. The leader of the matched allotype could be considered to be as important as the leader of the mismatched allotype for GVHD. Prospective identification of leader-matched donors is feasible for most patients in need of a HCT, and could lower GVHD and increase availability of HCT therapy. These findings are being independently validated and warrant further research in prospective trials. FUNDING The National Institutes of Health, USA.

中文翻译：

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HLA-B 外显子 1 在无关造血细胞移植后移植物抗宿主病中的作用：一项回顾性队列研究。


背景无关的造血细胞移植（HCT）的成功受到移植物抗宿主病（GVHD）的限制，当无法获得HLA匹配的供体时，这是移植后的主要挑战。 HLA-B 外显子 1 中的序列二态性产生含有蛋氨酸 (Met; M) 或苏氨酸 (Thr; T) 的前导肽，它们对自然杀伤和 T 细胞同种异体反应有不同的影响。该研究的主要目的是评估先导二态性在 HLA-B 不匹配的无关 HCT 后 GVHD 中的作用。方法 我们对 1988 年 1 月 1 日至 2016 年 12 月 31 日期间在澳大利亚、欧洲、日本、北美和英国接受不相关 HCT 的 33 982 名患者进行了一项回顾性队列研究。数据由国际参与者提供造血细胞移植组织相容性工作组。所有病例均被纳入，并且没有排除标准。使用多变量回归模型评估与 HLA-A、HLA-B、HLA-C、HLA-DRB1 和 HLA-DQB1 不匹配相关的风险。在 33 982 例移植中，使用多变量模型在 17 100 例 (50·3%) HLA 匹配移植和 1457 例 (4·3%) 单一 HLA-B 不匹配移植中确定了与 HLA-B M 和 T 前导序列相关的 GVHD 风险。回归模型。领导者频率是在 2 004 742 名 BeTheMatch 美国注册捐赠者中定义的。研究结果 在 2017 年 1 月 20 日至 2019 年 3 月 11 日期间，我们使用多元回归模型评估了 33 982 例 HCT，了解 HLA 不匹配对结果的影响。中位随访时间为 1841 天 (IQR 909-2963)。死亡率和 GVHD 随着 HLA 不匹配数量的增加而增加。单一 HLA-B 错配会增加 3-4 级急性 GVHD（比值比 [OR] 1·89，95% CI 1·53-2·33；p<0·0001）。 在单次 HLA-B 不匹配的移植中，前导序列不匹配的急性 GVHD 风险高于前导序列匹配的急性 GVHD 风险（OR 1·73、1·02-2·94；对于 2-4 级，p=0·042）。 M 前导序列共享同种异型与 T 前导序列共享同种异型比较（OR 1·98、1·39-2·81；对于 3-4 级，p=0·0001）。优选的 HLA-B 不匹配供体是前导序列匹配的并且共享 T 前导序列同种异型。 2 004 742 名美国登记捐献者中的大多数（1 836 939 [91·6%]）具有 TT 或 MT 基因型。解释 HLA-B 前导序列告知 HLA-B 不匹配的无关 HCT 后的 GVHD 风险，并将高风险 HLA-B 不匹配与低风险的 HLA-B 不匹配区分开来。对于 GVHD，匹配同种异型的前导序列可以被认为与不匹配同种异型的前导序列一样重要。对于大多数需要 HCT 的患者来说，前瞻性鉴定领导者匹配的供体是可行的，并且可以降低 GVHD 并增加 HCT 治疗的可用性。这些发现正在得到独立验证，并值得在前瞻性试验中进行进一步研究。资助美国国立卫生研究院。