Tanimine Naoki, Markmann James F, Wood-Trageser Michelle A, Demetris Anthony J, Mason Kristen, Silva Juliete A F, Levitsky Josh, Feng Sandy, Humar Abhinav, Emond Jean C, Shaked Abraham, Klintmalm Goran, Sanchez-Fueyo Alberto, Lesniak Drew, Breeden Cynthia P, Nepom Gerald T, Bridges Nancy D, Goldstein Julia, Larsen Christian P, DesMarais Michele, Gaile Geo, Chandran Sindhu
Department of Gastroenterological and Transplant Surgery, Hiroshima University, Higashihiroshima, Japan.
Penn Transplant Institute, Philadelphia, Pennsylvania, USA.
Am J Transplant. 2025 May;25(5):1030-1044. doi: 10.1016/j.ajt.2024.10.022. Epub 2024 Nov 4.
Immunosuppression can be withdrawn from selected liver transplant recipients, although robust clinical predictors of tolerance remain elusive. The Immune Tolerance Network ITN056ST study (OPTIMAL; NCT02533180) assessed clinical outcomes and mechanistic correlates of phased immunosuppression withdrawal (ISW) in nonautoimmune, nonviral adult liver transplant recipients. Enrolled subjects were ≥3 years posttransplant with minimal/absent inflammation or fibrosis on a screening liver biopsy. The primary end point was operational tolerance at 52 weeks following complete ISW. Of 61 subjects who initiated ISW, 34 failed during ISW and 10 restarted immunosuppression after completing ISW due to clinically manifest acute rejection. Only 10 of 17 clinically stable subjects remaining off immunosuppression at 1 year were ultimately deemed tolerant by biopsy. There were no cases of chronic rejection or graft loss; 28.3% developed de novo donor-specific antibody during ISW, which persisted in 11.3%. The majority of subjects (78.6%), including those who experienced rejection, ended the study on same or less calcineurin inhibitor than at baseline. 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.
对于部分肝移植受者，可以停用免疫抑制药物，尽管目前仍难以找到可靠的临床耐受性预测指标。免疫耐受网络ITN056ST研究（OPTIMAL；NCT02533180）评估了非自身免疫性、非病毒性成年肝移植受者分阶段停用免疫抑制（ISW）的临床结局及其机制相关性。入组受试者为移植后≥3年，筛查肝活检显示炎症或纤维化轻微/不存在。主要终点是完全停用免疫抑制后52周的手术耐受性。在61名开始停用免疫抑制的受试者中，34名在停用过程中失败，10名在完成停用后因临床表现为急性排斥反应而重新开始免疫抑制治疗。在17名1年后仍未使用免疫抑制药物且临床稳定的受试者中，最终只有10名经活检被认为具有耐受性。没有慢性排斥反应或移植物丢失的病例；28.3%的受试者在停用免疫抑制期间产生了新的供体特异性抗体，其中11.3%的抗体持续存在。大多数受试者（78.6%），包括那些经历过排斥反应的受试者，在研究结束时使用的钙调神经磷酸酶抑制剂与基线时相同或减少。少数（16.4%）组织学和临床稳定的成年长期肝移植受者能够成功停用并维持不使用免疫抑制药物的状态。供体特异性T细胞衰老频率增加、C4d沉积以及筛查肝活检时免疫突触密度升高，成为手术耐受性的潜在候选生物标志物。
