Human leukocyte antigen epitope mismatch loads and the development of de novo donor-specific antibodies in cardiothoracic organ transplantation
Human leukocyte antigen epitope mismatch loads and the development of de novo donor-specific antibodies in cardiothoracic organ transplantation
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DOI：
10.1111/iji.12563
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发表时间：
2021-12-14
影响因子：
2.2
通讯作者：
Poulton, Kay
中科院分区：
文献类型：
--
作者：
Bedford, Amy;Jervis, Steven;Poulton, Kay
在实体器官移植中，供体特异性人类白细胞抗原（HLA）抗体（dnDSA）与排斥反应和死亡风险增加相关。这种dnDSA在一些受体中在移植后错配的HLA的同种异体识别时产生。HLA配型目前在死亡供体心脏和肺的分配中未被考虑，移植前免疫风险分层完全基于循环供体定向HLA抗体的平均荧光强度（MFI）。基于HLA表位的匹配工具预测存在于供体HLA中但不存在于受体HLA中的B细胞或T细胞HLA表位。我们假设具有较高表位错配负荷的患者发生dnDSA的风险增加。我们回顾性分析了2015年至2020年间接受DSA检查的73名心脏和/或肺移植受者。分别使用HLAMatchmaker、PIRCHE-II和HLA表位错配算法（HLA-EMMA）计算eplet错配（EpMM）负荷、T细胞表位错配（TEpMM）负荷和溶剂可及氨基酸错配（SAMM）负荷。多变量分析显示，HLA-EMMA是所有HLA位点的总评分与dnDSA产生之间存在显著相关性的唯一工具[比值比（OR）1.021，95%置信区间（CI）1.003-1.042，p = .0225]，尽管这种风险增加是微不足道的。大多数dnDSA针对HLA-DQ，具有较高HLA-DQ TEpMM负荷（OR = 1.008，CI = 1.002-1.014，p = .007）和HLA-DR+DQ SAMM负荷（OR = 1.035，CI = 1.010-1.064，p = .0077）的患者最有可能产生dnDSA。我们还发现，在由HLA-DQA 1 *05 + HLA-DQB 1 *02/03：01编码的HLA分子内具有风险表位的患者更有可能产生dnDSA。基于HLA表位的匹配工具的使用可用于心胸移植风险分层，以使早期干预和监测的患者在生产dnDSA的风险增加。
De novo donor-specific human leucocyte antigen (HLA) antibodies (dnDSA) are associated with increased risk of rejection and mortality in solid organ transplantation. Such dnDSA is produced in some recipients upon allorecognition of mismatched HLA post-transplant. HLA matching is not currently considered in the allocation of deceased donor hearts and lungs and pre-transplant immunological risk stratification is based entirely on the mean fluorescence intensity (MFI) of circulating donor-directed HLA antibodies. HLA epitope-based matching tools predict B-cell or T-cell HLA epitopes that are present in the donor's HLA but absent in the recipient's HLA. We hypothesized that patients with higher epitope mismatch loads would be at increased risk of dnDSA development. We retrospectively analysed 73 heart and/or lung transplant recipients who were tested for DSA between 2015 and 2020. HLAMatchmaker, PIRCHE-II and HLA epitope mismatch algorithm (HLA-EMMA) were used to calculate eplet mismatch (EpMM) loads, T-cell epitope mismatch (TEpMM) loads and solvent accessible amino acid mismatch (SAMM) loads, respectively. Multivariate analyses showed that HLA-EMMA was the only tool with a significant association between the total score for all HLA loci and dnDSA production [odds ratio (OR) 1.021, 95% confidence interval (CI) 1.003-1.042, p = .0225] though this increased risk was marginal. The majority of dnDSA were directed against HLA-DQ and patients with higher HLA-DQ TEpMM loads (OR = 1.008, CI = 1.002-1.014, p = .007), and HLA-DR+DQ SAMM loads (OR = 1.035, CI = 1.010-1.064, p = .0077) were most at risk of producing dnDSA. We also showed that patients with a risk epitope within the HLA molecule encoded for by HLA-DQA1*05 + HLA-DQB1*02/03:01 were significantly more likely to produce dnDSA. The use of HLA epitope-based matching tools could be used for cardiothoracic transplant risk stratification to enable early intervention and monitoring of patients at increased risk of producing dnDSA.