Cross-organ hierarchy of HLA molecular mismatches in donor-specific antibody development in solid organ transplantations.

IF 11.7 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2025-06-17 Epub Date: 2025-05-30 DOI:10.1016/j.xcrm.2025.102153

Masaaki Hirata, Kazuto Tsukita, Takero Shindo, Shintaro Yagi, Takashi Ito, Satona Tanaka, Ryo Fujimoto, Hidenao Kayawake, Kenji Nakamura, Nobuhiro Fujiyama, Mitsuru Saito, Kimiko Yurugi, Rie Hishida, Arisa Kato, Atsushi Kawaguchi, Tomonori Habuchi, Takashi Kobayashi, Hiroshi Date, Etsuro Hatano

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引用次数: 0

Abstract

Donor-specific antibodies (DSAs) against human leukocyte antigen (HLA) play a crucial role in antibody-mediated rejection, a major barrier to successful organ transplantation. Donor-recipient HLA molecular incompatibility critically influences DSA susceptibility, commonly assessed by analyzing mismatches in the HLA eplet repertoire. This study, including six distinct liver, lung, and kidney transplant cohorts from two centers (978 donor-recipient pairs), explores associations between individual eplet mismatches and DSA development. Certain mismatched eplets are strongly linked to DSA development, while others show weaker associations, a trend consistent across different organ types. Machine learning leverages these hierarchical associations to develop an eplet risk score (ERS), outperforming traditional eplet mismatch assessments. Furthermore, T cell proliferation in mixed lymphocyte reaction in vitro correlates with the ERS, attenuated by antibody-mediated inhibition of a mismatched DSA-associated eplet. These results establish the differential immunological impacts of mismatched HLA eplets as integral in clinical practice and therapeutic innovation.

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实体器官移植中供体特异性抗体发展中HLA分子错配的跨器官层次。

针对人白细胞抗原（HLA）的供体特异性抗体（dsa）在抗体介导的排斥反应中起着至关重要的作用，这是器官移植成功的主要障碍。供体-受体HLA分子不相容严重影响DSA的易感性，通常通过分析HLA小序列的不匹配来评估。这项研究包括来自两个中心的6个不同的肝、肺和肾移植队列（978对供体-受体对），探讨了个体eplet错配与DSA发展之间的关系。某些不匹配的eplets与DSA的发展密切相关，而另一些则表现出较弱的关联，这种趋势在不同的器官类型中是一致的。机器学习利用这些层次关联来开发eplet风险评分（ERS），优于传统的eplet错配评估。此外，体外混合淋巴细胞反应中的T细胞增殖与ERS相关，通过抗体介导的不匹配dsa相关基因的抑制而减弱。这些结果确立了错配HLA小体的差异免疫影响在临床实践和治疗创新中不可或缺。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.