Donor-specific Immune Senescence as a Candidate Biomarker of Operational Tolerance Following Liver Transplantation in Adults: Results of a Prospective, Multicenter Cohort Study.

IF 8.9 2区 医学 Q1 SURGERY American Journal of Transplantation Pub Date : 2024-11-04 DOI:10.1016/j.ajt.2024.10.022
Naoki Tanimine, James F Markmann, Michelle A Wood-Trageser, Anthony J Demetris, Kristen Mason, Juliete A F Silva, Josh Levitsky, Sandy Feng, Abhinav Humar, Jean C Emond, Abraham Shaked, Goran Klintmalm, Alberto Sanchez-Fueyo, Drew Lesniak, Cynthia P Breeden, Gerald T Nepom, Nancy D Bridges, Julia Goldstein, Christian P Larsen, Michele DesMarais, Geo Gaile, Sindhu Chandran
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Abstract

Immunosuppression can be withdrawn from selected liver transplant recipients, although robust clinical predictors of tolerance remain elusive. The Immune Tolerance Network ITN056ST study (OPTIMAL) assessed clinical outcomes and mechanistic correlates of phased immunosuppression withdrawal (ISW) in non-autoimmune, non-viral adult liver transplant recipients. Enrolled subjects were ≥3 years post-transplant with minimal/absent inflammation or fibrosis on a screening liver biopsy. The primary endpoint was operational tolerance at 52 weeks following complete ISW. Of 61 subjects who initiated ISW, 34 failed during ISW and 10 restarted immunosuppression due to clinically manifest acute rejection. Of the 17 subjects remaining off immunosuppression at 1 year, 10 were ultimately deemed tolerant by biopsy. There were no cases of chronic rejection or graft loss. The majority of subjects (78.6%), including those who experienced rejection, ended the study on same or less calcineurin inhibitor than at baseline. 28.3% developed de novo DSA during ISW, which persisted in 11.3%. A minority (16.4%) of histologically and clinically stable long-term adult liver transplant recipients can successfully discontinue and remain off immunosuppression. Increased frequency of donor-specific T cell senescence, C4d deposition and higher density of immune synapses on the screening liver biopsy emerged as potential candidate biomarkers for operational tolerance. NCT02533180.

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作为成人肝移植后操作耐受性候选生物标志物的捐献者特异性免疫衰老:一项前瞻性多中心队列研究的结果。
免疫抑制可以从选定的肝移植受者身上撤除,但耐受性的可靠临床预测指标仍然难以捉摸。免疫耐受网络ITN056ST研究(OPTIMAL)评估了非自身免疫性、非病毒性成人肝移植受者分阶段撤除免疫抑制(ISW)的临床结果和机理相关性。入组受试者移植后≥3年,筛查肝活检时炎症或纤维化极少/无。主要终点是完成 ISW 后 52 周的操作耐受性。在61名开始ISW的受试者中,34人在ISW期间失败,10人因临床表现急性排斥反应而重新开始免疫抑制。在 1 年后仍未使用免疫抑制剂的 17 名受试者中,有 10 人最终通过活组织检查被认定为耐受。没有出现慢性排斥反应或移植物丢失的病例。大多数受试者(78.6%),包括出现排斥反应的受试者,在研究结束时使用的钙神经蛋白抑制剂与基线时相同或更少。28.3%的受试者在ISW期间出现了新的DSA,11.3%的受试者DSA持续存在。少数(16.4%)组织学和临床表现稳定的长期成人肝移植受者可以成功停用免疫抑制剂。供体特异性 T 细胞衰老频率的增加、C4d 的沉积以及筛查肝脏活检中免疫突触密度的升高成为操作耐受性的潜在候选生物标记物。NCT02533180。
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来源期刊
CiteScore
18.70
自引率
4.50%
发文量
346
审稿时长
26 days
期刊介绍: The American Journal of Transplantation is a leading journal in the field of transplantation. It serves as a forum for debate and reassessment, an agent of change, and a major platform for promoting understanding, improving results, and advancing science. Published monthly, it provides an essential resource for researchers and clinicians worldwide. The journal publishes original articles, case reports, invited reviews, letters to the editor, critical reviews, news features, consensus documents, and guidelines over 12 issues a year. It covers all major subject areas in transplantation, including thoracic (heart, lung), abdominal (kidney, liver, pancreas, islets), tissue and stem cell transplantation, organ and tissue donation and preservation, tissue injury, repair, inflammation, and aging, histocompatibility, drugs and pharmacology, graft survival, and prevention of graft dysfunction and failure. It also explores ethical and social issues in the field.
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Donor-specific Immune Senescence as a Candidate Biomarker of Operational Tolerance Following Liver Transplantation in Adults: Results of a Prospective, Multicenter Cohort Study. Outside Front Cover Racial disparities across multiple stages of the deceased organ donation process Robotic living donor hepatectomy is associated with superior outcomes for both the donor and the recipient compared with laparoscopic or open - A single-center prospective registry study of 3448 cases Invasive aspergillosis in liver transplant recipients in the current era
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