Thromboregulatory strategies to prolong xenograft survival.

延长异种移植物存活的血栓调节策略。

• 批准号: 7086952
• 负责人: SIMON C. ROBSON
• 金额: $ 59.58万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7086952
• 关键词: CD antigens; anticoagulants; antigen antibody reaction; baboons; biotechnology; blood chemistry; blood coagulation disorders; genetic manipulation; genetically modified animals; graft versus host disease; histocompatibility; immunosuppression; kidney transplantation; pancreatic islet transplantation; platelet activating factor; platelet activation; regulatory gene; swine; thrombin; thrombocytopathy; thrombomodulin; transcription factor; transplant rejection; transplantation immunology; urinalysis; xenotransplantation

DESCRIPTION (provided by applicant): Xenotransplantation may be clinically feasible once the molecular barriers between species and mechanisms of graft loss or rejection are better understood. Xenograft survival would have to be also achieved without compromising the recipient to the extent that systemic toxicity would be encountered. In this regard, genetic engineering of swine, with xenograft modification to provide greater compatibility, has been of recent interest. Thrombotic and inflammatory reactions to porcine bone marrow (BM)-derived cells, infused pancreatic islets and the vasculature of organ grafts are linked to the difficulties in establishing mixed discordant chimerism, pancreatic islet-associated procoagulant injury and the development of xenograft microangiopathy. These responses are likely associated with humoral immune reactions to xenogeneic tissues. However, thrombotic processes with progressive xenograft vascular injury and infarction may be further exacerbated by documented intrinsic molecular incompatibilities in regulation of blood clotting between discordant species. An example of this would be the failure of natural porcine anticoagulants, such as thrombomodulin, to interact with human/primate coagulation factors, such as thrombin and Protein C. The development of the GalT-KO pig and consequent removal of the dominant xeno-antigen have been a major advance in xenotransplantation research. However, problems still persist in inducing tolerance by generating mixed xenogeneic chimerism, either by vascularized thymic tissues or the BM-derived cell approach in baboons. GalT-KO islets have not yet been tested but the current GalT-KO renal and cardiac xenograft limited survival times and associated vascular injury patterns still preclude clinical application. The goals of this application are to effectively manage graft thrombotic and vascular sequelae associated with GalT-KO pig-to-baboon renal grafting and those complications seen in islet xenotransplantation. We will evaluate transgenic approaches to over-express CD39, a key thromboregulatory protein and/or thrombomodulin in pigs. Transgenic porcine vascularized renal grafts and pancreatic islets over-expressing these human factors will be transplanted into baboons. Our strategies will include optimal immunosuppressive interventions with protocols to attempt induction of tolerance. These studies will be judged successful if novel, clinically relevant antithrombotic therapies can be then developed and applied.

描述（由申请人提供）：一旦更好地理解了物种之间的分子屏障以及移植物丢失或排斥的机制，异种移植在临床上可能是可行的。异种移植物的存活还必须在不损害受体的情况下达到全身毒性的程度。在这方面，通过异种移植修饰以提供更大的相容性的猪基因工程最近引起了人们的兴趣。猪骨髓（BM）来源的细胞、输注的胰岛和器官移植物的脉管系统的血栓和炎症反应与建立混合不一致嵌合体的困难、胰岛相关的促凝血损伤和异种移植微血管病的发展有关。这些反应可能与异种组织的体液免疫反应有关。然而，已记录的不一致物种之间血液凝固调节中的内在分子不相容性可能会进一步加剧进行性异种移植血管损伤和梗塞的血栓形成过程。一个例子是天然猪抗凝剂（例如血栓调节蛋白）无法与人类/灵长类凝血因子（例如凝血酶和蛋白 C）相互作用。 GalT-KO 猪的发育以及随后主要异种抗原的去除是异种移植研究的重大进展。然而，通过产生混合异种嵌合体来诱导耐受性的问题仍然存在，无论是通过血管化胸腺组织还是狒狒体内的骨髓衍生细胞方法。 GalT-KO 胰岛尚未经过测试，但目前的 GalT-KO 肾和心脏异种移植物有限的生存时间和相关的血管损伤模式仍然妨碍临床应用。该应用的目标是有效管理与 GalT-KO 猪-狒狒肾移植相关的移植物血栓和血管后遗症以及胰岛异种移植中出现的并发症。我们将评估在猪中过度表达 CD39（一种关键的血栓调节蛋白和/或血栓调节蛋白）的转基因方法。过度表达这些人类因子的转基因猪血管肾移植物和胰岛将被移植到狒狒体内。我们的策略将包括最佳的免疫抑制干预措施和尝试诱导耐受的方案。如果能够开发和应用新颖的、临床相关的抗血栓疗法，这些研究将被视为成功。