Genetics of HLA Peptide Presentation and Impact on Outcomes in HLA-Matched Allogeneic Hematopoietic Cell Transplantation.
Genetics of HLA Peptide Presentation and Impact on Outcomes in HLA-Matched Allogeneic Hematopoietic Cell Transplantation.
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HLA肽表现的遗传学以及对HLA匹配的同种异体造血细胞移植的结果的影响。
DOI：
10.1016/j.jtct.2021.04.003
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发表时间：
2021-07
影响因子：
3.2
通讯作者：
Center for International Blood and Marrow Transplant Research Immunobiology Working Committee
中科院分区：
文献类型：
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作者：
Story CM;Wang T;Bhatt VR;Battiwalla M;Badawy SM;Kamoun M;Gragert L;Brown V;Baxter-Lowe LA;Marsh SGE;Gadalla SM;Schetelig J;Mytilineos J;Miklos D;Waller EK;Kuxhausen M;Spellman S;Lee S;Paczesny S;Lansford JL;Vincent BG;Riches ML;Armistead PM;Center for International Blood and Marrow Transplant Research Immunobiology Working Committee
次要组织相容性抗原（Minor histocompatibility antigens，mHA）是细胞表面呈递的抗原衍生肽表位，已知其介导移植物抗宿主病（graft-versus-host disease，GVHD）;然而，目前尚无将mHA特征与GVHD风险相关联的方法。这一缺陷部分是由于缺乏技术手段来准确预测，更不用说确认，在每个个体移植中潜在的mHA的巨大数量。先前的研究表明，不同的HLA分子呈现不同比例的候选肽表位;然而，HLA匹配的供体和受体之间的遗传“距离”相对受限。根据这2个观察结果，供体-受体对（DRP）的HLA类型可能会提供预测mHA数量的替代测量，这可能与GVHD风险相关。由于不同的HLA分子呈现可变数量的肽抗原，因此可以基于对的HLA类型计算单个DRP的预测累积肽结合效率。本研究的目的是测试累积肽结合效率是否与急性GVHD（aGVHD）或复发的风险相关。在国际血液和骨髓移植研究中心的这项回顾性研究中，共分析了3242例HLA匹配的DRP，使用其HLA类型预测累积肽结合效率，并根据其评分分为三分位数。进行单变量和多变量分析以测试DRP的累积肽结合效率（分为HLA匹配的相关供体（MRD）和HLA匹配的无关供体（MUD）队列）与aGVHD和复发的主要结局之间的关联。研究的次要结局包括总生存率、无病生存率和移植相关死亡率。使用计算生成的肽组作为测试数据集，测试的HLA I类系列显示出完整肽组的0.1%至3.8%的肽结合频率，HLA II类分子在HLA-DRB 1同种异型中具有12%至77%的肽结合频率。通过增加结合效率三分位数，MUD患者6个月时HLA I类aGVHD的累积发生率分别为41%、41%和45%（P = 0.336），HLA II类aGVHD的累积发生率分别为44%、41%和42%（P = 0.452）。MUD移植受者3年时HLA I类的累积复发率分别为36%、38%和38%（P = 0.533），HLA II类的累积复发率分别为37%、37%和38%（P = 0.896）。MRD移植受者的结果相似。多变量分析并未发现肽结合效率对MUD或MRD移植受者的aGVHD或复发有任何影响。尽管GVHD是由HLA匹配的allo-HCT背景下的微小抗原错配介导的，但用作预测结合抗原数量的替代测量的肽结合效率并没有为GVHD风险评估提供额外的临床信息。阴性结果可能是由于该替代标志物的局限性，或者GVHD可能是由免疫原性mHA的子集驱动的。进一步的研究应针对直接mHA表位和免疫原性预测。
Minor histocompatibility antigens (mHAs), recipient-derived peptide epitopes presented on the cell surface, are known to mediate graft-versus-host disease (GVHD); however, there are no current methods to associate mHA features with GVHD risk. This deficiency is due in part to the lack of technological means to accurately predict, let alone confirm, the tremendous number of potential mHAs in each individual transplant. Previous studies have shown that different HLA molecules present varying fractions of candidate peptide epitopes; however, the genetic “distance” between HLA-matched donors and recipients is relatively constrained. From these 2 observations, it is possible that the HLA type for a donor-recipient pair (DRP) would provide a surrogate measurement of the number of predicted mHAs, which could be related to GVHD risk. Because different HLA molecules present variable numbers of peptide antigens, a predicted cumulative peptide-binding efficiency can be calculated for individual DRP based on the pair’s HLA type. The purpose of this study was to test whether cumulative peptide-binding efficiency is associated with the risk of acute GVHD (aGVHD) or relapse. In this retrospective Center for International Blood and Marrow Transplant Research study, a total of 3242 HLA-matched DRPs were analyzed for predicted cumulative peptide-binding efficiency using their HLA types and were divided into tertiles based on their scores. Univariable and multivariable analyses was performed to test for associations between cumulative peptide-binding efficiency for DRPs, divided into the HLA-matched related donor (MRD) and HLA-matched unrelated donor (MUD) cohorts, and the primary outcomes of aGVHD and relapse. Secondary outcomes investigated included overall survival, disease-free survival, and transplantation-related mortality. Using a computationally generated peptidome as a test dataset, the tested series of HLA class I displayed peptide-binding frequencies ranging from 0.1% to 3.8% of the full peptidome, and HLA class II molecules had peptide-binding frequencies of 12% to 77% across the HLA-DRB1 allotypes. By increasing binding efficiency tertile, the cumulative incidence of aGVHD at 6 months for MUD patients was 41%, 41%, and 45% for HLA class I (P = .336) and 44%, 41%, and 42% for HLA class II (P = .452). The cumulative incidences of relapse at 3 years for MUD transplant recipients were 36%, 38%, and 38% for HLA class I (P = .533) and 37%, 37%, and 38% for HLA class II (P = .896). The findings were similar for MRD transplant recipients. Multivariable analysis did not identify any impact of peptide-binding efficiency on aGVHD or relapse in MUD or MRD transplant recipients. Whereas GVHD is mediated by minor antigen mismatches in the context of HLA-matched allo-HCT, peptide-binding efficiency, which was used as a surrogate measurement for predicted number of binding antigens, did not provide additional clinical information for GVHD risk assessment. The negative result may be due to the limitations of this surrogate marker, or it is possible that GVHD is driven by a subset of immunogenic mHAs. Further research should be directed at direct mHA epitope and immunogenicity prediction.
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DOI：
10.1016/j.bbmt.2008.12.497
发表时间：
2009-03
期刊：
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
影响因子：
--
作者：
Giralt S;Ballen K;Rizzo D;Bacigalupo A;Horowitz M;Pasquini M;Sandmaier B
通讯作者：
Sandmaier B
影响因子：
32.4
作者：
Abelin JG;Keskin DB;Sarkizova S;Hartigan CR;Zhang W;Sidney J;Stevens J;Lane W;Zhang GL;Eisenhaure TM;Clauser KR;Hacohen N;Rooney MS;Carr SA;Wu CJ
通讯作者：
Wu CJ
影响因子：
4.3
作者：
Bacigalupo, Andrea;Ballen, Karen;Rizzo, Doug;Giralt, Sergio;Lazarus, Hillard;Ho, Vincent;Apperley, Jane;Slavin, Shimon;Pasquini, Marcelo;Sandmaier, Brenda M.;Barrett, John;Blaise, Didier;Lowski, Robert;Horowitz, Mary
通讯作者：
Horowitz, Mary
影响因子：
29.7
作者：
Blum JS;Wearsch PA;Cresswell P
通讯作者：
Cresswell P
DOI：
10.1084/jem.20071985
发表时间：
2008-03-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fortier MH;Caron E;Hardy MP;Voisin G;Lemieux S;Perreault C;Thibault P
通讯作者：
Thibault P