Bone marrow chimerism and tolerance induced by single-dose cyclophosphamide.
Bone marrow chimerism and tolerance induced by single-dose cyclophosphamide.
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DOI：
10.1016/j.jss.2004.01.011
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发表时间：
2004-07
期刊：
影响因子：
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通讯作者：
Junji Okayama;S. Ko;H. Kanehiro;H. Kanokogi;M. Hisanaga;K. Ohashi;M. Sho;M. Nagao;N. Ikeda
中科院分区：
文献类型：
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作者：
Junji Okayama;S. Ko;H. Kanehiro;H. Kanokogi;M. Hisanaga;K. Ohashi;M. Sho;M. Nagao;N. Ikeda
造血嵌合体的建立是供者特异性免疫耐受最稳定的策略。临床应用需要更安全的预处理方案。我们评估了一个简单的协议，使用环磷酰胺（环磷酰胺）诱导嵌合体和器官移植耐受性跨越主要组织相容性复合体（MHC）的障碍在大鼠。材料和方法BN（RT 1 n）供体的骨髓细胞输注到LEW（RT 1 l）受体后，在第0天单次注射环磷酰胺在第-1天的各种剂量。通过流式细胞术评估供体来源的造血嵌合体。受体在第100天接受BN或第三方（BUF）心脏移植。在200 mg/kg剂量的BHD预处理诱导高水平的造血嵌合体时，8例受体中有6例死于严重的移植物抗宿主病（GVHD）。在150 mg/kg剂量下，在第10天诱导了36.5 ± 24.1%的供体来源的嵌合体，并且观察到持续的巨嵌合体，直到第100天，没有GVHD。用100 mg/kg剂量的地塞米松预处理仅导致一过性嵌合（4.8 ± 5.2%），在第20天消失。在接受50 mg/kg的异环磷酰胺的受者中，供体骨髓细胞被迅速排斥，未观察到嵌合体。150 mg/kg剂量组接受BN心脏移植（>100 d × 5），12 d时排斥BUF心脏移植（n = 4）。BN心脏移植物在100（MST：57 d，n = 5）和50 mg/kg（MST：7 d，n = 5）剂量组均发生排斥反应。150 mg/kg的剂量似乎是诱导器官移植耐受而不发生GVHD的最佳剂量。
BACKGROUNDEstablishment of hematopoietic chimerism is the most stable strategy for donor-specific tolerance. Safer pretreatment regimens are needed for clinical application. We evaluated the efficacy of a simple protocol using cyclophosphamide (CYP) on induction of chimerism and organ transplant tolerance across major histocompatibility complex (MHC) barriers in the rat.MATERIALS AND METHODSBone marrow cells from BN (RT1n) donors were infused to LEW (RT1l) recipients on day 0 after a single injection of CYP at various doses on day −1. Donor-derived hematopoietic chimerism was evaluated by flowcytometry. The recipients received BN or third party (BUF) heart allografts on day 100.RESULTSWhile pretreatment with 200 mg/kg of CYP induced high levels of hematopoietic chimerism, six of eight recipients died of severe graft-versus-host-disease (GVHD). CYP at dose of 150 mg/kg induced 36.5 ± 24.1% of donor-derived chimerism on day 10, and sustained macrochimerism was seen until day 100 without GVHD. Pretreatment with 100 mg/kg of CYP resulted in only transient chimerism (4.8 ± 5.2%) which disappeared by day 20. In the recipients with 50 mg/kg of CYP, donor bone marrow cells were rapidly rejected and no chimerism was observed. The recipients with 150 mg/kg of CYP accepted BN heart allografts (>100 days × 5), while rejecting BUF allografts by day 12 (n = 4). BN heart allografts were rejected in the recipients with 100 (MST: 57 days, n = 5) and 50 mg/kg (MST: 7 days, n = 5) of CYP.CONCLUSIONSA single dose of CYP can induce hematopoietic chimerism across MHC-barriers. The dose of 150 mg/kg seems to be optimal to induce organ transplant tolerance without developing GVHD.