Life-supporting Kidney Xenotransplantation From Genetically Engineered Pigs in Baboons: A Comparison of Two Immunosuppressive Regimens
Life-supporting Kidney Xenotransplantation From Genetically Engineered Pigs in Baboons: A Comparison of Two Immunosuppressive Regimens
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DOI：
10.1097/tp.0000000000002796
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发表时间：
2019-10-01
期刊：
影响因子：
6.2
通讯作者：
Iwase, Hayato
中科院分区：
文献类型：
--
作者：
Yamamoto, Takayuki;Hara, Hidetaka;Iwase, Hayato
背景本研究的目的是评价美国食品和药物管理局批准的药物在基因工程猪-狒狒异种肾移植中的疗效，并将结果与使用基于抗CD 40单克隆抗体（mAb）的方案的结果进行比较。方法.使用α 1，3-半乳糖基转移酶基因敲除/CD 46猪在狒狒中进行了10例维持生命的肾移植，并进行了旨在控制凝血功能失调的各种其他遗传操作。8例移植获得了信息丰富的数据。免疫抑制治疗包括抗胸腺细胞球蛋白和抗CD 20 mAb诱导，以及基于（1）CTLA 4-IG和/或他克莫司（+雷帕霉素或霉酚酸酯）（A组[美国食品和药物管理局批准的方案]，n = 4）或（2）抗CD 40 mAb+雷帕霉素（B组，n = 4）的维持治疗。所有狒狒均接受皮质类固醇、白细胞介素-6R阻断和肿瘤坏死因子-α阻断。对狒狒进行肾功能、凝血和免疫参数的临床和实验室监测。在安乐死时，对肾移植物进行形态学和免疫组织化学研究。结果B组中位生存期为186天（90-260天），明显长于A组中位生存期14天（12-32天）（P < 0.01）。仅A组狒狒出现消耗性凝血病和血栓性微血管病性肾小球病和间质性动脉血管炎的组织病理学特征。结论.认识到每组中的猪供体在一些遗传修饰方面存在差异，这些数据表明，包括抗CD 40 mAb在内的维持免疫抑制对预防猪肾移植失败可能很重要。
Background. The aims of this study were to evaluate the efficacy of US Food and Drug Administration-approved drugs in genetically engineered pig-to-baboon kidney xenotransplantation and compare the results with those using an anti-CD40 monoclonal antibody (mAb)-based regimen. Methods. Ten life-supporting kidney transplants were carried out in baboons using alpha 1,3-galactosyltransferase gene-knockout/CD46 pigs with various other genetic manipulations aimed at controlling coagulation dysregulation. Eight transplants resulted in informative data. Immunosuppressive therapy consisted of induction with antithymocyte globulin and anti-CD20mAb, and maintenance based on either (1) CTLA4-Ig and/or tacrolimus (+rapamycin or mycophenolate mofetil) (GroupA [US Food and Drug Administration-approved regimens], n = 4) or (2) anti-CD40mAb + rapamycin (GroupB, n = 4). All baboons received corticosteroids, interleukin-6R blockade, and tumor necrosis factor-alpha blockade. Baboons were followed by clinical and laboratory monitoring of kidney function, coagulation, and immune parameters. At euthanasia, morphological and immunohistochemical studies were performed on the kidney grafts. Results. The median survival in GroupB was 186 days (range 90-260), which was significantly longer than in GroupA; median 14 days (range 12-32) (P < 0.01). Only GroupA baboons developed consumptive coagulopathy and the histopathological features of thrombotic microangiopathic glomerulopathy and interstitial arterial vasculitis. Conclusions. Recognizing that the pig donors in each group differed in some genetic modifications, these data indicate that maintenance immunosuppression including anti-CD40mAb may be important to prevent pig kidney graft failure.