Thymic transplantation in pig-to-nonhuman primates for the induction of tolerance across xenogeneic barriers.
Thymic transplantation in pig-to-nonhuman primates for the induction of tolerance across xenogeneic barriers.
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DOI：
10.1007/978-1-61779-845-0_12
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发表时间：
2012-01-01
期刊：
影响因子：
--
通讯作者：
Scalea, Joseph
中科院分区：
文献类型：
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作者：
Yamada, Kazuhiko;Scalea, Joseph
随着α 1，3-半乳糖基转移酶（GalT-KO，缺乏人类已预先形成抗体的细胞表面抗原）敲除猪的出现，研究人员延长了支持生命的异种肾移植物的存活时间。然而，尽管有这些增加，移植有GalT-KO肾移植物的非人灵长类动物对强于或强于同种异体反应的抗供体T细胞反应敏感。为了防止排斥反应，接受者必须经受病态高水平的免疫抑制。由于这些原因，我们的实验室已经尝试开发新的异种耐受的方法，使用血管化的猪胸腺移植物，以重新教导受体的免疫系统接受异种器官作为自身。这些策略主要由山田和彦博士开发，涉及血管化供体胸腺与肾脏的共同移植。这一点已通过两种方式成功做到。第一种方法涉及制备复合组织“胸腺肾”，第二种方法利用移植分离的带血管的胸腺叶。两种策略都涉及在异种移植时移植完全血管化的胸腺组织，这一事实对于异种移植后胸腺组织的功能和受体T细胞的再教育至关重要。这些策略成功地诱导了小型猪完全同种异体模型的耐受性，并将我们的猪-狒狒生命支持异种移植模型中的移植物存活期延长至80天以上，体外证据表明供体特异性无反应性。虽然这是为时尚早的临床肾异种移植方案的发展，本章介绍了作者的独特经验，最有前途的临床前大动物模型异种移植。此外，理解异种移植中T细胞反应的重要性和测量取决于这些程序的功能知识。
With the advent of knockout pigs for alpha1,3-galactosyltransferease (GalT-KO, which lack a cell-surface antigen to which humans have preformed antibodies), investigators have extended the survival of life-supporting xenorenal grafts. However, despite these increases, nonhuman primates transplanted with GalT-KO renal grafts are susceptible to anti-donor T-cell responses that are strong or stronger than allogeneic responses. In order to prevent rejection, recipients must be subjected to morbidly high levels of immunosuppression. For these reasons, our laboratory has attempted to develop novel methods of xenogeneic tolerance using vascularized porcine thymic grafts in order to reteach the recipient's immune system to accept the xenogeneic organ as self. These strategies, largely developed by Dr. Kazuhiko Yamada, involve the co-transplantation of a vascularized donor thymus with a kidney. This has been successfully done in two ways. The first method involves the preparation of a composite tissue "thymokidney" and the second utilizes the transplantation of an isolated vascularized thymic lobe. Both strategies involve the transplantation of fully vascularized thymic tissue at the time of xenotransplantation, a fact which is crucial for function of the thymic tissue immediately after xenografting and reeducation of recipient T-cells. These strategies have successfully induced tolerance across fully allogeneic models in miniature swine and prolonged graft survival in our pig-to-baboon model of life-supporting xenotransplantation to greater than 80 days with in vitro evidence of donor-specific unresponsiveness. Although it is too early for the development of clinical renal xenotransplantation protocols, this chapter describes the authors' unique experience with one of the most promising preclinical large-animal models of xenotransplantation. Furthermore, understanding the importance and measurement of T-cell responses in xenotransplantation is contingent upon a functional knowledge of these procedures.