Pre-clinical heterotopic intrathoracic heart xenotransplantation: a possibly useful clinical technique
Pre-clinical heterotopic intrathoracic heart xenotransplantation: a possibly useful clinical technique
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DOI：
10.1111/xen.12213
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发表时间：
2015-11-01
影响因子：
3.9
通讯作者：
Brenner, Paolo
中科院分区：
文献类型：
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作者：
Abicht, Jan-Michael;Mayr, Tanja;Brenner, Paolo
作为临床异种心脏移植的一步，我们的实验性异位胸腔内异种移植模型提供了一个跳动和喷射的供体心脏，同时保留受体的自体器官作为移植失败时的备用器官。临床上适用的免疫抑制方案（IS）进行了调查，然后治疗已知是有效的超敏患者或那些与adrenocitrant排斥reactions. MethodsConciliative实验进行了2009年和2013年之间。使用21头基因修饰的猪（GGTA 1敲除/hCD 46/血栓调节蛋白，在一种情况下用HLA-E代替）作为供体。在所有实验中，两个免疫吸收循环减少了预先形成的抗体。根据IS方案将狒狒分为两组：第一组（n = 10），在移植前1周（抗CD 20）或4周（抗CD 20+蛋白酶体抑制剂硼替佐米）开始预处理。扩展的常规（如同种异体移植）免疫抑制维持方案包括抗胸腺细胞球蛋白、他克莫司、吗替麦考酚酯、甲泼尼龙和每周抗CD 20。在第二组（n = 11）中，与多发性骨髓瘤患者一样进行清髓性预治疗（长和短方案）添加到扩展的常规IS;术后全胸和腹部淋巴照射（TLI; 600 cGY的单剂量）用于进一步减少抗体产生细胞。ResultsIn围手术期过程中，手术技术安全应用：19只狒狒脱离体外循环，17只拔管。由于与手术技术或IS方案无关的原因，9只动物在术后早期丢失。排除这些早期失败，第1组和第2组的中位移植物存活时间分别为18.5（12-50）天和16（7-35）天。第1组供体器官的尸检显示6个持久移植物的左心室壁肥大;心肌组织学证实了临床前怀疑的体液排斥反应，其不受延长的常规IS（包括强化治疗）和血栓性微血管病体征的抑制。第2组的移植物仅表现出轻度至中度的体液排斥反应和血栓性微血管病特征，除了1例在第17天出现迟发性排斥反应。在这组中的其他实验被终止，因为无法治疗的肺水肿，复发性室颤，曲霉菌败血症，以及一个大的供体器官和晚期毒副作用的组合，由于TLI. ConclusionsLong-term的结果是难以实现在这个模型中，由于使用的IS方案。然而，我们的结论是，异位胸腔内心脏移植可能是临床异种移植的一种选择。
BackgroundAs a step towards clinical cardiac xenotransplantation, our experimental heterotopic intrathoracic xenotransplantation model offers a beating and ejecting donor heart while retaining the recipients native organ as a backup in case of graft failure. Clinically applicable immunosuppressive regimens (IS) were investigated first, then treatments known to be effective in hypersensitized patients or those with recalcitrant rejection reactions.MethodsConsecutive experiments were carried out between 2009 and 2013. Twenty-one genetically modified pigs (GGTA1-knockout/hCD46/ thrombomodulin, in one case HLA-E instead) were used as donors. In all experiments, two cycles of immunoabsorption reduced preformed antibodies. Recipient baboons were divided into two groups according to IS regimen: In group one (n = 10), pre-treatment started either one (anti-CD20) or four weeks (anti-CD20 plus the proteasome inhibitor bortezomib) prior to transplantation. The extended conventional (as for allotransplantation) immunosuppressive maintenance regimen included anti-thymocyte globuline, tacrolimus, mycophenolate mofetil, methylprednisolone and weekly anti-CD20. In group two (n = 11), myeloablative pre-treatment as in multiple myeloma patients (long and short regimens) was added to extended conventional IS; postoperative total thoracic and abdominal lymphoid irradiation (TLI; single dose of 600 cGY) was used to further reduce antibody-producing cells.ResultsIn the perioperative course, the surgical technique was safely applied: 19 baboons were weaned off extracorporeal circulation and 17 extubated. Nine animals were lost in the early postoperative course due to causes unrelated to surgical technique or IS regimen. Excluding these early failures, median graft survival times of group 1 and 2 were 18.5 (12-50) days and 16 (7-35) days. Necropsy examination of group 1 donor organs revealed hypertrophy of the left ventricular wall in the six longer-lasting grafts; myocardial histology confirmed pre-clinical suspicion of humoral rejection, which was not inhibited by the extended conventional IS including intensified treatments, and signs of thrombotic microangiopathy. Grafts of group 2 presented with only mild-to-moderate features of humoral rejection and thrombotic microangiopathy, except in one case of delayed rejection on day 17. The other experiments in this group were terminated because of untreatable pulmonary oedema, recurring ventricular fibrillation, Aspergillus sepsis, as well as a combination of a large donor organ and late toxic side effects due to TLI.ConclusionsLonger-term results were difficult to achieve in this model due to the IS regimens used. However, we conclude that heterotopic intrathoracic heart transplantation may be an option for clinical xenotransplantation.