Identification of risk epitope mismatches associated with de novo donor-specific HLA antibody development in cardiothoracic transplantation
Identification of risk epitope mismatches associated with de novo donor-specific HLA antibody development in cardiothoracic transplantation
复制标题
DOI：
10.1111/ajt.14951
复制
发表时间：
2018-12-01
影响因子：
8.8
通讯作者：
Tinckam, K. J.
中科院分区：
文献类型：
--
作者：
McCaughan, J. A.;Battle, R. K.;Tinckam, K. J.
移植后新出现的供者特异性的人类白细胞抗原抗体(DnDSA)与移植失败、死亡率和费用有关。目前尚无有效的治疗干预措施来预防dnDSA或改善相关损伤。这项研究的目的是确定与dnDSA发生相关的特定的人类白细胞抗原因素，并提出初级预防策略，在不限制移植机会的情况下减少dnDSA的发生率。研究队列包括2008至2015年间的心脏移植受者(n=265)。移植前、后分别进行人类白细胞抗原(HL A)配型和抗体检测。对持久性dnDSA进行HLAMatchaker分析，以确定潜在的更具免疫原性的eplet差异。在2008年至2013年接受肺移植的患者中进行验证(n=433)。大多数dnDSA受者对DQ2和DQ7上相同的eplet位置有抗体。高危表位错配(在DQA1*05+DQB1*02/DQB1*03：01(7)中发现)与心脏和肺受体患dnDSA的风险分别增加4.2和4.9倍相关。对于这种观察到的免疫原性，人类白细胞抗原静电势模型提供了一个可信的解释。产生了一种避免高风险表位错配的理论分配算法，并预测在不需要额外测试、eplet分析或成本的情况下，dnDSA最高可减少72%。
The development of de novo donor-specific HLA antibodies (dnDSA) after transplantation is associated with graft failure, mortality, and cost. There is no effective therapeutic intervention to prevent dnDSA or ameliorate associated injury. The aims of this study were to identify specific HLA factors associated with dnDSA development and to propose primary prevention strategies that could reduce the incidence of dnDSA without prohibitively limiting access to transplant. The investigation cohort included heart transplant recipients from 2008 to 2015 (n = 265). HLA typing was performed and HLA antibody testing was undertaken before and after transplantation. HLAMatchmaker analysis was performed for persistent dnDSA to identify potentially more immunogenic eplet differences. Validation was performed in recipients of lung transplants from 2008 to 2013 (n = 433). The majority of recipients with dnDSA had antibodies to identical eplet positions on DQ2 and DQ7. A high-risk epitope mismatch (found in DQA1*05 + DQB1*02/DQB1*03:01(7)) was associated with a 4.2- and 4.9-fold increased risk of dnDSA in heart and lung recipients respectively. HLA electrostatic potential modeling provided a plausible explanation for this observed immunogenicity. A theoretical allocation algorithm avoiding high-risk epitope mismatches was generated and predicted to reduce dnDSA by up to 72% without additional testing, eplet analysis, or cost.