对肾移植中的 NK 细胞进行高维分析,发现与抗体依赖性移植物功能障碍相关的亚群。

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Dan Fu Ruan, Miguel Fribourg, Yuko Yuki, Yeon-Hwa Park, Maureen P Martin, Haocheng Yu, Geoffrey C Kelly, Brian Lee, Ronaldo M de Real, Rachel Lee, Daniel Geanon, Seunghee Kim-Schulze, Nicholas Chun, Paolo Cravedi, Mary Carrington, Peter S Heeger, Amir Horowitz
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引用次数: 0

摘要

自然杀伤(NK)细胞通过 NKG2A/HLA-E 或杀伤细胞免疫球蛋白样受体(KIR)/HLA-ABC 相互作用对病变细胞和异体细胞做出反应。HLA/KIR差异与肾移植病理之间的相关性表明,NK细胞在移植中的致病作用与抗体无关,但其机制仍不清楚。利用 CyTOF 表征受者外周 NK 细胞的表型和功能,我们观察到参与者中有不同的 NK 细胞亚群,它们对异体刺激剂的反应也不尽相同。与其他亚群相比,NKG2A+/KIR+ NK细胞的反应更强烈,尽管存在免疫抑制,但这种高反应在肾移植后仍持续存在。在两项临床试验的测试组和验证组中,NKG2A+ NK 细胞在移植前由供体诱导释放的细胞毒性介质 Ksp37 与长期异体移植功能降低有关。另外的分析表明,在缺乏组织学排斥反应的异体活组织中,Ksp37 基因表达与死亡删减后的移植物损失相关。我们的研究结果支持 NK 细胞在移植损伤中发挥与抗体无关的作用,并支持进一步测试移植前供体反应性 NK 细胞产生的 Ksp37 作为风险评估和移植生物标志物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
High-dimensional analysis of NK cells in kidney transplantation uncovers subsets associated with antibody-independent graft dysfunction.

Natural killer (NK) cells respond to diseased and allogeneic cells through NKG2A/HLA-E or killer cell immunoglobulin-like receptor (KIR)/HLA-ABC interactions. Correlations between HLA/KIR disparities and kidney transplant pathology suggest an antibody-independent pathogenic role for NK cells in transplantation, but the mechanisms remain unclear. Using CyTOF to characterize recipient peripheral NK cell phenotypes and function, we observed diverse NK cell subsets among participants who responded heterogeneously to allo-stimulators. NKG2A+KIR+ NK cells responded more vigorously than other subsets, and this heightened response persisted after kidney transplantation despite immunosuppression. In test and validation sets from 2 clinical trials, pretransplant donor-induced release of cytotoxicity mediator Ksp37 by NKG2A+ NK cells correlated with reduced long-term allograft function. Separate analyses showed that Ksp37 gene expression in allograft biopsies lacking histological rejection correlated with death-censored graft loss. Our findings support an antibody-independent role for NK cells in transplant injury and support further testing of pretransplant, donor-reactive, NK cell-produced Ksp37 as a risk-assessing, transplantation biomarker.

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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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