Comprehensive Transplant Center, Northwestern Memorial Hospital, Chicago, IL, USA.
Transplantation. 2013 Jan 15;95(1):169-76. doi: 10.1097/TP.0b013e3182782fc1.
We recently reported that durable chimerism can be safely established in mismatched kidney recipients through nonmyeloablative conditioning followed by infusion of a facilitating cell (FC)-based hematopoietic stem cell transplantation termed FCRx. Here we provide intermediate-term follow-up on this phase II trial.
Fifteen human leukocyte antigen-mismatched living donor renal transplant recipients underwent low-intensity conditioning (fludarabine, cyclophosphamide, 200 cGy TBI), received a living donor kidney transplant on day 0, then infusion of cryopreserved FCRx on day +1. Maintenance immunosuppression, consisting of tacrolimus and mycophenolate, was weaned over 1 year.
All but one patient demonstrated peripheral blood macrochimerism after transplantation. Engraftment failure occurred in a highly sensitized (panel reactive antibody [PRA] of 52%) recipient. Chimerism was lost in three patients at 2, 3, and 6 months after transplantation. Two of these subjects had received either a reduced cell dose or incomplete conditioning; the other two had PRA greater than 20%. All demonstrated donor-specific hyporesponsiveness and were weaned from full-dose immunosuppression. Complete immunosuppression withdrawal at 1 year after transplantation was successful in all patients with durable chimerism. There has been no graft-versus-host disease or engraftment syndrome. Renal transplantation loss occurred in one patient who developed sepsis following an atypical viral infection. Two subjects with only transient chimerism demonstrated subclinical rejection on protocol biopsy despite donor-specific hyporesponsiveness.
Low-intensity conditioning plus FCRx safely achieved durable chimerism in mismatched allograft recipients. Sensitization represents an obstacle to successful induction of chimerism. Sustained T-cell chimerism is a more robust biomarker of tolerance than donor-specific hyporeactivity.
我们最近报道，通过非清髓性预处理联合促进细胞（FC）为基础的造血干细胞移植（称为 FCRx）输注，可以在不匹配的肾移植受者中安全建立持久的嵌合体。在此，我们提供该 II 期试验的中期随访结果。
15 例人类白细胞抗原不匹配的活体供肾移植受者接受低强度预处理（氟达拉滨、环磷酰胺、200cGyTBI），在第 0 天接受活体供肾移植，然后在第 +1 天输注冷冻保存的 FCRx。维持免疫抑制方案包括他克莫司和霉酚酸酯，在 1 年内逐渐停用。
除 1 例患者外，所有患者在移植后均出现外周血巨嵌合体。在 1 例高致敏（群体反应性抗体 [PRA]为 52%）患者中发生移植物衰竭。3 例患者在移植后 2、3 和 6 个月时丢失嵌合体。其中 2 例患者接受了减少细胞剂量或不完全预处理；另外 2 例患者 PRA 大于 20%。所有患者均表现出供者特异性低反应性，并逐渐停用全剂量免疫抑制剂。在移植后 1 年时，所有具有持久嵌合体的患者均成功完全停用免疫抑制剂。未发生移植物抗宿主病或植入综合征。1 例患者在非典型病毒感染后发生脓毒症而导致移植肾丢失。2 例仅有短暂嵌合体的患者尽管存在供者特异性低反应性，但在方案活检中显示出亚临床排斥反应。
低强度预处理联合 FCRx 可安全地在不匹配的同种异体移植受者中实现持久的嵌合体。致敏是成功诱导嵌合体的障碍。持续的 T 细胞嵌合体是比供者特异性低反应性更可靠的耐受生物标志物。
