Circulating Tissue Specific Extracellular Vesicles for Noninvasive Monitoring of Acute Cellular Rejection in Clinical Heart Transplantation.

IF 5 2区医学 Q1 IMMUNOLOGY

Transplantation Pub Date : 2025-09-01 Epub Date: 2025-04-16 DOI:10.1097/TP.0000000000005369

Laxminarayana Korutla, Robert Hu, Yihan Liu, Connie Romano, Andreas Habertheuer, Parisa Abedi, He Wang, Sudheer Molugu, Susan Rostami, Ali Naji, Abdulelah Nuqali, Michael Beasley, Christopher Maulion, Samuel Hahn, Tariq Ahmad, Zuoheng Wang, Sounok Sen, Prashanth Vallabhajosyula

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引用次数: 0

Abstract

Background: There remains a critical need for biomarkers of acute cellular rejection (ACR) in heart transplantation. We hypothesized that immunopathophysiology of ACR is reflected via dynamic changes in the protein and RNA cargoes of small extracellular vesicles (sEVs) released by cardiac allograft and T cells into circulation, thus enabling noninvasive window into ACR.

Methods: T-cell sEVs were enriched using anti-CD3 antibody beads, and antidonor HLA I antibody beads for donor sEVs. Cargoes of donor sEVs (cardiac troponin T [cTnT] protein and mRNA) and T-cell sEVs (CD4, CD8, T-cell receptor proteins, miRNAs [miRs] let 7i, 101b, 21a) were compared with time-matched endomyocardial biopsy samples (n = 70) in 12 patients to postoperative day 120.

Results: Six patients had 11 moderate ACR (15.7%) episodes, 1 had antibody-mediated rejection, and 5 had ≤ mild ACR. By Wilcoxon rank-sum tests, cTnT protein ( P = 6.04 × 10 -5 ) and mRNA ( P = 6.87 × 10 -7 ) were decreased with moderate ACR compared with grades 0/1 ACR. T-cell sEV CD4, CD8, and TCR protein cargoes ( P ≤ 3.92 × 10 -5 ) and miRs let 7i, 101b, and 21a ( P ≤ 9.05 × 10 -5 ) were increased with moderate ACR. Successful treatment of moderate ACR led to dynamic reversal in sEV profiles, especially donor heart sEV cTnT mRNA (Spearman coefficient 0.87) and miR 21a (coefficient 0.85).

Conclusions: Our first investigation in heart transplant patients demonstrated that circulating T cell-sEV and donor heart-sEV profiles enable diagnosis of moderate ACR with high diagnostic accuracy. A large sample cohort external validation study is warranted to better understand diagnostic potential of this platform for ACR monitoring in heart transplantation.

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循环组织特异性细胞外囊泡无创监测临床心脏移植急性细胞排斥反应。

背景：在心脏移植中仍然迫切需要急性细胞排斥反应（ACR）的生物标志物。我们假设ACR的免疫病理生理是通过心脏移植物和T细胞释放的小细胞外囊泡（sev）的蛋白质和RNA的动态变化来反映的，从而实现了ACR的无创窗口。方法：用抗cd3抗体珠和抗供体HLA - 1抗体珠富集t细胞sev。将12例患者术后120天的供体sev（心肌肌钙蛋白T [cTnT]蛋白和mRNA）和T细胞sev （CD4、CD8、T细胞受体蛋白、mirna [miRs] let 7i、101b、21a）与时间匹配的心内膜活检样本（n = 70）进行比较。结果：6例患者发生中度ACR 11次（15.7%），1例发生抗体介导的排斥反应，5例发生≤轻度ACR。通过Wilcoxon秩和检验，与0/1级ACR相比，中度ACR组cTnT蛋白（P = 6.04 × 10-5）和mRNA （P = 6.87 × 10-7）降低。中度ACR时t细胞sEV CD4、CD8和TCR蛋白载货量（P≤3.92 × 10-5）和miRs let 7i、101b和21a （P≤9.05 × 10-5）升高。成功治疗中度ACR导致sEV谱动态逆转，尤其是供体心脏sEV cTnT mRNA （Spearman系数0.87）和miR 21a（系数0.85）。结论：我们对心脏移植患者的首次调查表明，循环T细胞- sev和供体心脏sev谱能够诊断中度ACR，诊断准确性高。为了更好地了解该平台在心脏移植ACR监测中的诊断潜力，有必要进行一项大样本队列外部验证研究。

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.