Comparing Plasma Donor-derived Cell-free DNA to Gene Expression in Endomyocardial Biopsies in the Trifecta-Heart Study.

IF 5.3 2区医学 Q1 IMMUNOLOGY Transplantation Pub Date : 2024-09-01 Epub Date: 2024-08-20 DOI:10.1097/TP.0000000000004986

Philip F Halloran, Jeff Reeve, Martina Mackova, Katelynn S Madill-Thomsen, Zachary Demko, Michael Olymbios, Patrick Campbell, Vojtech Melenovsky, Timothy Gong, Shelley Hall, Josef Stehlik

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Abstract

Background: Plasma donor-derived cell-free DNA (dd-cfDNA) is used to screen for rejection in heart transplants. We launched the Trifecta-Heart study ( ClinicalTrials.gov No. NCT04707872), an investigator-initiated, prospective trial, to examine the correlations between genome-wide molecular changes in endomyocardial biopsies (EMBs) and plasma dd-cfDNA. The present report analyzes the correlation of plasma dd-cfDNA with gene expression in EMBs from 4 vanguard centers and compared these correlations with those in 604 kidney transplant biopsies in the Trifecta-Kidney study ( ClinicalTrials.gov No. NCT04239703).

Methods: We analyzed 137 consecutive dd-cfDNA-EMB pairs from 70 patients. Plasma %dd-cfDNA was measured by the Prospera test (Natera Inc), and gene expression in EMBs was assessed by Molecular Microscope Diagnostic System using machine-learning algorithms to interpret rejection and injury states.

Results: Top transcripts correlating with dd-cfDNA were related to genes increased in rejection such as interferon gamma-inducible genes (eg, HLA-DMA ) but also with genes induced by injury and expressed in macrophages (eg, SERPINA1 and HMOX1 ). In gene enrichment analysis, the top dd-cfDNA-correlated genes reflected inflammation and rejection pathways. Dd-cfDNA correlations with rejection genes in EMB were similar to those seen in kidney transplant biopsies, with somewhat stronger correlations for TCMR genes in hearts and ABMR genes in kidneys. However, the correlations with parenchymal injury-induced genes and macrophage genes were much stronger in hearts.

Conclusions: In this first analysis of Trifecta-Heart study, dd-cfDNA correlates significantly with molecular rejection but also with injury and macrophage infiltration, reflecting the proinflammatory properties of injured cardiomyocytes. The relationship supports the utility of dd-cfDNA in clinical management of heart transplant recipients.

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比较血浆捐献者来源的无细胞 DNA 与 Trifecta-Heart 研究中心内膜活检组织的基因表达。

背景：血浆供体源性无细胞 DNA（dd-cfDNA）用于筛查心脏移植中的排斥反应。我们启动了一项由研究者发起的前瞻性试验--Trifecta-Heart 研究（ClinicalTrials.gov 编号：NCT04707872），以检验心内膜活检组织（EMB）中全基因组分子变化与血浆 dd-cfDNA 之间的相关性。本报告分析了血浆 dd-cfDNA 与 4 个先锋中心的 EMB 中基因表达的相关性，并将这些相关性与 Trifecta-Kidney 研究（ClinicalTrials.gov 编号：NCT04239703）中 604 例肾移植活检的相关性进行了比较：我们分析了来自 70 名患者的 137 对连续的 dd-cfDNA-EMB 对。血浆中的ddd-cfDNA%由Prospera测试（Natera Inc）测定，EMB中的基因表达由分子显微诊断系统评估，使用机器学习算法解释排斥和损伤状态：结果：与dd-cfDNA相关的最高转录本与排斥反应中增加的基因有关，如γ干扰素诱导基因（如HLA-DMA），但也与损伤诱导并在巨噬细胞中表达的基因有关（如SERPINA1和HMOX1）。在基因富集分析中，dd-cfDNA相关性最高的基因反映了炎症和排斥反应途径。EMB 中 Dd-cfDNA 与排斥基因的相关性与肾移植活检中的相关性相似，心脏中的 TCMR 基因和肾脏中的 ABMR 基因的相关性更强一些。然而，在心脏中，与实质损伤诱导基因和巨噬细胞基因的相关性要强得多：结论：在三联心脏研究的首次分析中，dd-cfDNA 与分子排斥反应显著相关，但也与损伤和巨噬细胞浸润相关，反映了损伤心肌细胞的促炎特性。这种关系支持了 dd-cfDNA 在心脏移植受者临床管理中的应用。

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

Transplantation 医学-免疫学

CiteScore

8.50

自引率

11.30%

发文量

1906

审稿时长

1 months

期刊介绍： The official journal of The Transplantation Society, and the International Liver Transplantation Society, Transplantation is published monthly and is the most cited and influential journal in the field, with more than 25,000 citations per year. Transplantation has been the trusted source for extensive and timely coverage of the most important advances in transplantation for over 50 years. The Editors and Editorial Board are an international group of research and clinical leaders that includes many pioneers of the field, representing a diverse range of areas of expertise. This capable editorial team provides thoughtful and thorough peer review, and delivers rapid, careful and insightful editorial evaluation of all manuscripts submitted to the journal. Transplantation is committed to rapid review and publication. The journal remains competitive with a time to first decision of fewer than 21 days. Transplantation was the first in the field to offer CME credit to its peer reviewers for reviews completed. The journal publishes original research articles in original clinical science and original basic science. Short reports bring attention to research at the forefront of the field. Other areas covered include cell therapy and islet transplantation, immunobiology and genomics, and xenotransplantation.