Long-term donor-specific tolerance in rat cardiac allografts by intrabone marrow injection of donor bone marrow cells
Long-term donor-specific tolerance in rat cardiac allografts by intrabone marrow injection of donor bone marrow cells
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DOI：
10.1097/01.tp.0000296061.71662.76
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发表时间：
2008-01-15
期刊：
影响因子：
6.2
通讯作者：
Ikehara, Susumu
中科院分区：
文献类型：
--
作者：
Guo, Kequan;Inaba, Muneo;Ikehara, Susumu
背景。通过常规静脉骨髓移植（IV-BMT）的造血嵌合可以诱导同种异体心脏移植的供体特异性中枢耐受。然而，IV-BMT存在一些问题，如移植物失败的风险和调理方案的毒性。提出了一种新的心脏移植方法。该方法包括给药磷酸氟达拉滨（50 mg/kg）和分次低剂量照射（3.5 Gyx2或4.0 Gyx2），然后骨髓内注射全骨髓细胞（IBM-BMT）加异位心脏移植。采用ibm - bmt的同种异体心脏移植物被接受并长期存活（bbb10个月），在这种调节方案下，既没有出现急性排斥反应，也没有出现慢性排斥反应，包括同种异体心脏移植物血管病变。相比之下，采用常规IV-BMT的同种异体心脏移植物在3.5 Gyx2照射后1个月内或4.0 Gyx2照射后3个月内发生排斥反应。IBM-BMT较好地建立并稳定维持了巨嵌合（> 70%），而IV-BMT则没有。氟达拉滨+ 4.0 Gyx2的IV-BMT诱导低水平的短暂混合嵌合（< 7%），但嵌合在治疗后1个月内消失。这些发现表明，IBM-BMT是一种诱导持续供体特异性耐受的可行策略，可以使用减少的辐射剂量作为调节方案，并且无需使用免疫抑制剂。
Background. Donor-specific central tolerance in cardiac allograft can be induced by hematopoietic chimerism via conventional intravenous bone marrow transplantation (IV-BMT). However, there are problems with IV-BMT, such as the risk of graft failure and of the toxicity from conditioning regimens.Methods. A new method for heart transplantation is presented. This method consists of administration of fludarabine phosphate (50 mg/kg) and fractionated low-dose irradiation (3.5 Gyx2 or 4.0 Gyx2), followed by intrabone marrow injection of whole bone marrow cells (IBM-BMT) plus heterotopic heart transplantation.Results. Cardiac allografts with IBM-BMTwere accepted and survived long-term (> 10 months) showing neither acute rejection nor chronic rejection including cardiac allograft vasculopathy by such conditioning regimens. In contrast, cardiac allografts with conventional IV-BMT were rejected within 1 month after the treatment with irradiation of 3.5 Gyx2 or within 3 months after the treatment with irradiation of 4.0 Gyx2. Macrochimerism (> 70%) was favorably established and stably maintained by IBM-BMT but not IV-BMT. Low levels of transient mixed chimerism (< 7%) were induced by IV-BMT with fludarabine plus 4.0 Gyx2, but the chimerism was lost within I month after the treatment.Conclusions. These findings indicate that IBM-BMT is a feasible strategy for the induction of persistent donor-specific tolerance, enables the use of reduced radiation doses as conditioning regimens, and obviates the need for immunosuppressants.