Vionnet Julien, Torres-Yaguana Jorge, Miquel Rosa, Abraldes Juan G, Wall Jurate, Kodela Elisavet, Lozano Juan-Jose, Ruiz Pablo, Navasa Miguel, Marshall Aileen, Nevens Frederik, Gelson Will, Leithead Joanna, Masson Steven, Jaeckel Elmar, Taubert Richard, Tachtatzis Phaedra, Eurich Dennis, Simpson Kenneth J, Bonaccorsi-Riani Eliano, Ferguson James, Quaglia Alberto, Demetris Anthony J, Lesniak Andrew J, Elstad Maria, Delord Marc, Douiri Abdel, Rebollo-Mesa Irene, Martinez-Llordella Marc, Silva Juliete A F, Markmann James F, Sánchez-Fueyo Alberto
Institute of Liver Studies, School of Immunology and Microbial Sciences, King's College London University and King's College Hospital, London, UK; Transplantation Center, Service of Immunology and Allergy, and Servide of Gastroenterology and Hepatology, University Hospital of Lausanne, Lausanne, Switzerland.
Institute of Liver Studies, School of Immunology and Microbial Sciences, King's College London University and King's College Hospital, London, UK.
Am J Transplant. 2025 May;25(5):1045-1058. doi: 10.1016/j.ajt.2024.12.002. Epub 2024 Dec 18.
The maintenance of stable allograft status in the absence of immunosuppression (IS), known as operational tolerance, can be achieved in a small proportion of liver transplant recipients, but we lack reliable tools to predict its spontaneous development. We conducted a prospective, multicenter, biomarker-strategy design, IS withdrawal clinical trial to determine the utility of a predictive biomarker of operational tolerance. The biomarker test, originally identified in a patient cohort with high operational tolerance prevalence, consisted of a 5-gene transcriptional signature measured in liver tissue collected before initiating IS weaning. One hundred sixteen adult stable liver transplant recipients were randomized 1:1 to either arm A (IS withdrawal regardless of biomarker status) or arm B (IS withdrawal in biomarker-positive recipients). Immunosuppression withdrawal was initiated in 82 participants, rejection occurred in 54 (67.5%), and successful discontinuation of IS was achieved in 22 (27.5%), but only 13 (16.3%) met operational tolerance histologic criteria (10 in arm A; 3 in arm B). The biomarker test did not yield useful information in selecting patients able to successfully discontinue IS. Operational tolerance was associated with time posttransplant, recipient age, presence of circulating exhausted CD8 T cells, and a reduced number of immune synapses within the graft.
在无免疫抑制（IS）的情况下维持稳定的同种异体移植状态，即所谓的手术耐受，在一小部分肝移植受者中可以实现，但我们缺乏可靠的工具来预测其自发发展。我们开展了一项前瞻性、多中心、生物标志物策略设计的IS撤药临床试验，以确定手术耐受预测生物标志物的效用。该生物标志物检测最初在手术耐受患病率较高的患者队列中发现，由在开始撤减IS之前收集的肝组织中测量的5基因转录特征组成。116名成年稳定肝移植受者按1:1随机分为A组（无论生物标志物状态如何均撤减IS）或B组（生物标志物阳性受者撤减IS）。82名参与者开始撤减免疫抑制，54名（67.5%）发生排斥反应，22名（27.5%）成功停用IS，但只有13名（16.3%）符合手术耐受组织学标准（A组10名；B组3名）。该生物标志物检测在选择能够成功停用IS的患者方面未产生有用信息。手术耐受与移植后时间、受者年龄、循环中耗竭的CD8 T细胞的存在以及移植物内免疫突触数量减少有关。
