Yamada Kazuhiko, Scalea Joseph
Organ Transplantation Tolerance and Xenotransplantation Laboratory, Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Methods Mol Biol. 2012;885:191-212. doi: 10.1007/978-1-61779-845-0_12.
With the advent of knockout pigs for α1,3-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.
随着用于α1,3-半乳糖基转移酶的基因敲除猪（GalT-KO，缺乏人类预先形成抗体的细胞表面抗原）的出现，研究人员延长了维持生命的异种肾移植的存活时间。然而，尽管有这些延长，但移植了GalT-KO肾移植物的非人灵长类动物仍易发生抗供体T细胞反应，这种反应比同种异体反应更强或与之相当。为了防止排斥反应，受体必须接受极高水平的免疫抑制，这会导致病态。基于这些原因，我们实验室试图开发新的异种耐受方法，使用血管化的猪胸腺移植物，以便重新教导受体的免疫系统将异种器官视为自身。这些策略主要由山田和彦博士开发，包括将血管化的供体胸腺与肾脏共同移植。这已通过两种方式成功实现。第一种方法涉及制备复合组织“胸腺肾”，第二种方法利用分离的血管化胸腺叶进行移植。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以及受体T细胞的重新教导至关重要。这些策略已在小型猪的完全同种异体模型中成功诱导耐受，并在我们的猪到狒狒的维持生命的异种移植模型中延长了移植物存活时间，超过80天，且有体外证据表明存在供体特异性无反应性。虽然现在开发临床肾异种移植方案还为时过早，但本章描述了作者在最有前途的临床前异种移植大型动物模型之一中的独特经验。此外，了解异种移植中T细胞反应的重要性和测量方法取决于对这些程序的功能知识。
