Tolerance induction in HLA disparate living donor kidney transplantation by donor stem cell infusion: durable chimerism predicts outcome.
Tolerance induction in HLA disparate living donor kidney transplantation by donor stem cell infusion: durable chimerism predicts outcome.
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DOI：
10.1097/tp.0b013e3182782fc1
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发表时间：
2013-01-15
期刊：
影响因子：
6.2
通讯作者：
Ildstad ST
中科院分区：
文献类型：
--
作者：
Leventhal J;Abecassis M;Miller J;Gallon L;Tollerud D;Elliott MJ;Bozulic LD;Houston C;Sustento-Reodica N;Ildstad ST
我们最近报道，通过非清髓性调理，然后输注基于促进细胞（FC）的造血干细胞移植（称为 FCRx），可以在不匹配的肾受体中安全地建立持久嵌合状态。在此，我们提供该 2 期试验的中期随访。 15 名 HLA 不匹配的活体肾移植受者接受低强度调理（氟达拉滨、环磷酰胺、200cGyTBI），在第 0 天接受活体肾移植，然后在第 +1 天输注冷冻保存的 FCRx。由他克莫司和霉酚酸酯组成的维持性免疫抑制（IS）已停用一年多。除一名患者外，所有患者均在移植后表现出外周血大嵌合现象。高度敏感（PRA 为 52%）的受者发生植入失败。 3 名患者的嵌合状态在移植后 2、3 和 6 个月时消失。其中两名受试者接受了减少的细胞剂量或不完全的调节；另外 2 人的 PRA >20%。所有患者都表现出供体特异性低反应性，并停止了全剂量免疫抑制。所有具有持久嵌合状态的患者在移植后一年均成功完全撤除免疫抑制。没有发生 GVHD 或植入综合征。 1 名非典型病毒感染后出现败血症的患者发生肾移植失败。尽管存在供体特异性低反应，但仅具有短暂嵌合状态的两名受试者在方案活检中表现出亚临床排斥。低强度调节加上 FCRx 在不匹配的同种异体移植受体中安全地实现了持久嵌合。敏化是成功诱导嵌合现象的障碍。持续的 T 细胞嵌合是比供体特异性低反应性更强大的耐受性生物标志物。
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 transplant termed FCRx. Here we provide intermediate-term follow-up on this phase 2 trial. Fifteen HLA mismatched living donor renal transplant recipients underwent low intensity conditioning (fludarabine, cyclophosphamide, 200cGyTBI), received a living donor kidney transplant on day 0, then infusion of cryopreserved FCRx on day +1. Maintenance immunosuppression(IS),consisting of tacrolimus and mycophenolate, was weaned over one year. All but one patient demonstrated peripheral blood macrochimerism post-transplantation. Engraftment failure occurred in a highly sensitized (PRA of52%) recipient. Chimerism was lost in 3patients at 2, 3, and 6 months post transplantation. Two of these subjects had received either a reduced cell dose or incomplete conditioning; the other 2 had PRA >20%. All demonstrated donor-specific hyporesponsiveness and were weaned from full dose immunosuppression. Complete immunosuppression withdrawal at one year post-transplant was successful in all patients with durable chimerism. There has been no GVHD or engraftment syndrome. Renal transplant loss occurred in 1 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.