Donckier Vincent, Troisi Roberto, Toungouz Michel, Colle Isabelle, Van Vlierberghe Hans, Jacquy Caroline, Martiat Philippe, Stordeur Patrick, Zhou Ling, Boon Nathalie, Lambermont Micheline, Schandené Liliane, Van Laethem Jean Luc, Noens Lucien, Gelin Michel, de Hemptinne Bernard, Goldman Michel
Medicosurgical Department of Gastroenterology, Hôpital Erasme, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium.
Transpl Immunol. 2004 Sep-Oct;13(2):139-46. doi: 10.1016/j.trim.2004.05.004.
The induction of transplantation tolerance, defined as the survival of a functioning allograft in the absence of continuing immunosuppressive therapy, would be a major advance. Clinical and experimental data have shown that transplantation tolerance could be induced by pre-transplant myeloconditioning and infusion of donor hematopoietic cells. We investigated the feasibility and safety of a protocol to induce tolerance to HLA mismatched living-donor liver graft by pre-transplant non-myeloablative conditioning followed by donor stem cells (SC) infusion, in patients with advanced liver cancers.
Two patients with intrahepatic cancers who did not fulfill criteria for cadaver liver transplantation were included in the study. Preparative regimen consisted in cyclophosphamide and anti-thymocyte globulin, followed by infusion of purified donor CD34(+) stem cells. Living-donor liver transplantation (LDLT) using the liver right lobe was performed after hematological reconstitution, respectively 40 and 55 days after donor stem cell infusion. Immunosuppressive therapies were discontinued when liver graft function returned to normal.
The procedure could be completed in the two patients. No severe toxicity of the preparative regimen was observed. Neither patient presented graft versus host reaction after donor stem cell infusion. A transient macrochimerism was observed in the first case, while no chimerism could be detected in the second. Immunosuppression was discontinued, respectively 90 and 28 days, after liver transplantation, without subsequent rejection episode. In the two cases, liver function remained normal for the study period. In both patients, the period of immune reconstitution was prolonged, as illustrated by persisting low CD4(+) cell counts. Mixed lymphocyte cultures, performed after immunosuppression withdrawal, demonstrated donor specific hyporesponsiveness in the first case, but in a context of global hyporeactivity in the two patients. The first patient died from tumor recurrence 370 days after liver transplantation. The second patient is alive, 270 days after liver transplantation, but with a suspicion of tumor relapse as indicated by the reappearance of tumor marker in blood.
In the two cases, acceptance of HLA mismatched living-donor liver graft was obtained after non-myeloablative conditioning and donor stem cell infusion. Improving the rate of immune reconstitution appears as a priority to reduce the risk of tumor recurrence in such patients.
诱导移植耐受（定义为在无持续免疫抑制治疗的情况下，功能正常的同种异体移植物存活）将是一项重大进展。临床和实验数据表明，移植前骨髓预处理和输注供体造血细胞可诱导移植耐受。我们研究了一种方案的可行性和安全性，该方案通过移植前非清髓性预处理，随后输注供体干细胞（SC），来诱导晚期肝癌患者对 HLA 错配的活体供肝移植物产生耐受。
两名不符合尸体肝移植标准的肝内癌患者纳入本研究。预处理方案包括环磷酰胺和抗胸腺细胞球蛋白，随后输注纯化的供体 CD34(+)干细胞。在造血重建后，分别于供体干细胞输注后 40 天和 55 天进行右半肝活体供肝移植（LDLT）。当肝移植功能恢复正常时停止免疫抑制治疗。
该操作在两名患者中均得以完成。未观察到预处理方案的严重毒性。供体干细胞输注后，两名患者均未出现移植物抗宿主反应。第一例观察到短暂的大嵌合现象，而第二例未检测到嵌合现象。肝移植后分别于 90 天和 28 天停止免疫抑制，随后未发生排斥反应。在这两个病例中，研究期间肝功能均保持正常。两名患者的免疫重建期均延长，表现为 CD4(+)细胞计数持续偏低。免疫抑制撤除后进行的混合淋巴细胞培养显示，第一例有供体特异性低反应性，但两名患者均存在整体低反应性。第一例患者在肝移植后 370 天死于肿瘤复发。第二例患者在肝移植后 270 天存活，但血液中肿瘤标志物再次出现，怀疑有肿瘤复发。
在这两个病例中，通过非清髓性预处理和供体干细胞输注，实现了对 HLA 错配的活体供肝移植物的接受。提高免疫重建率似乎是降低此类患者肿瘤复发风险的首要任务。
