Induction of Major Histocompatibility Complex-mismatched Mouse Lung Allograft Acceptance With Combined Donor Bone Marrow: Lung Transplant Using a 12-Hour Nonmyeloablative Conditioning Regimen.
Induction of Major Histocompatibility Complex-mismatched Mouse Lung Allograft Acceptance With Combined Donor Bone Marrow: Lung Transplant Using a 12-Hour Nonmyeloablative Conditioning Regimen.
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DOI：
10.1097/tp.0000000000001480
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发表时间：
2016-12
期刊：
影响因子：
6.2
通讯作者：
Luznik L
中科院分区：
文献类型：
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作者：
Dodd-O JM;Ganguly S;Vulic A;Panoskaltsis-Mortari A;McDyer JF;Luznik L
尽管有广泛而强烈的常规免疫抑制，肺移植后的长期生存率仍落后于其他实体器官移植，主要原因是同种异体移植排斥反应。因此，迫切需要新的策略来促进肺移植的接受。本研究的目的是通过与死者供体器官利用相容的方案诱导同种异体移植物耐受。使用mhc错配的小鼠原位肺移植模型，我们研究了一种由移植前T细胞耗损、低剂量全身照射和移植后（供体）骨髓和脾细胞输注以及移植后环磷酰胺（PTTT-PTB/PTCy）组成的调节方案。我们的研究结果表明，接受BALB/c肺同种异体移植的C57BL/6受体接受这种完全的短时间非清髓调节方案具有持久的肺同种异体移植接受。缺乏一种或多种组分的小鼠表现出明显的移植物损失。从机制上讲，接受同种异体肺移植的动物建立了更高水平的供体嵌合，淋巴细胞对供体抗原的反应减弱，但对第三方抗原的反应保持不变，以及供体反应性宿主Vβ T细胞的克隆缺失。Foxp3+ T调节细胞的频率在存活和排斥的同种异体移植物中是相似的，这意味着它们的扰动不是主要的细胞调节机制。供体嵌合对于持续耐受是不可缺少的，这一点可以从PTTT-PTB/PTCy嵌合受体在继发受体淋巴细胞输注嵌合消融后同种异体移植物的急性排斥反应中得到证明。总之，这些数据为使用短时间非清髓性调节方案和PTCy的串联供体骨髓移植（BMT）建立肺同种异体移植耐受提供了概念证明。
Despite broad and intense conventional immunosuppression, long-term survival after lung transplantation lags behind that for other solid organ transplants, primarily because of allograft rejection. Therefore, new strategies to promote lung allograft acceptance are urgently needed. The purpose of the present study was to induce allograft tolerance with a protocol compatible with deceased donor organ utilization. Using the MHC-mismatched mouse orthotopic lung transplant model, we investigated a conditioning regimen consisting of pretransplant T cell depletion, low dose total body irradiation and posttransplant (donor) bone marrow and splenocyte infusion followed by posttransplantation cyclophosphamide (PTTT-PTB/PTCy). Our results show that C57BL/6 recipients of BALB/c lung allografts undergoing this complete short-duration nonmyeloablative conditioning regimen had durable lung allograft acceptance. Mice that lacked 1 or more components of this regimen exhibited significant graft loss. Mechanistically, animals with lung allograft acceptance had established higher levels of donor chimerism, lymphocyte responses which were attenuated to donor antigens but maintained to third-party antigens, and clonal deletion of donor-reactive host Vβ T cells. Frequencies of Foxp3+ T regulatory cells were comparable in both surviving and rejected allografts implying that their perturbation was not a dominant cell-regulatory mechanism. Donor chimerism was indispensable for sustained tolerance, as evidenced by acute rejection of allografts in established chimeric recipients of PTTT-PTB/PTCy following a chimerism-ablating secondary recipient lymphocyte infusion. Together, these data provide proof-of-concept for establishing lung allograft tolerance with tandem donor bone marrow transplantation (BMT) using a short-duration nonmyeloablative conditioning regimen and PTCy.