Thromboregulatory Barriers to Xenotransplantation

异种移植只有在异种移植物丢失和排斥机制出现后才能在临床上可行 更好地被理解。去显性近交系小型Galt-KO猪的研制 异种抗原是一项重大进展。然而，产生混合异物的问题仍然存在。 狒狒中的嵌合体与对异种细胞和血管化异种移植的耐受性。 猪骨髓来源细胞的炎症反应与器官移植物的血管形成有关 异常免疫反应、促凝血剂激活和异种移植的发展 微血管损伤。血栓形成过程和进行性异种移植物微血管病变 因功能失调的免疫反应而加重，已有文献记载的内在分子 不协调物种间血栓调节的不亲和性。我们在以下方面取得了重大进展 与CD39功能不相容相关的消耗性凝血障碍机制的确定 和血栓调节蛋白，并通过确定与以下相关的新的血管损伤标志 幽默拒绝。我们最近发现CD39由内皮细胞表达，也由T细胞表达 调节细胞。因此，这种外源核糖核酸酶产生的腺苷可以阻断血小板的激活。 凝血，也是一种免疫抑制调节剂。 我们的新研究将建立在这些成功和见解的基础上，以解决以下具体目标：#1： T细胞调节表达CD39的细胞免疫机制和腺苷生成的研究 细胞影响异种耐受机制(通过项目3中开发的模型)；和#2：演示 转基因上调人CD39和血栓调节蛋白在GALT-KO猪体内的治疗潜力 胸腺肾异种移植和耐受模型(项目1和2)。 这些策略将包括最佳免疫抑制干预方案，以尝试诱导 提高耐受性并改善狒狒的血管炎症。此应用程序的总体目标将是 有效管理免疫反应、移植物血管损伤和血栓形成，目前与GALT-KO相关 猪到狒狒胸腺肾的异种移植，从而提供临床相关的存活时间。

Xenotransplantation will only become clinically feasible once mechanisms of xenograft loss and rejection are better understood. The development of inbred miniature GalT-KO swine with removal of the dominant xeno-antigen has been a major advance. However, problems still persist in generating mixed xenogeneic chimerism in baboons and obtaining tolerance to xenogeneic cells and vascularized xenografts. Inflammatory reactions to porcine bone marrow-derived cells and the vasculature of organ grafts are linked to aberrant immune responses, together with procoagulant activation and the development of xenograft microvascular injury. Thrombotic processes and the progressive xenograft microangiopathy appear exacerbated by dysfunctional immune reactions and already documented intrinsic molecular incompatibilities in thromboregulation between discordant species. We have made significant progress in defining mechanisms of consumptive coagulopathy linked to associated functional incompatibilities of CD39 and thrombomodulin across species, and by determining novel vascular markers of injury associated with humoral rejection. We have recently shown that CD39 is expressed by the endothelium and also by T regulatory cells. Hence, adenosine generated by this ectonucleotidase blocks platelet activation impeding coagulation and also serves as an immune suppressive mediator. Our new studies will build on these successes and insights to address the following Specific Aims: #1: Study how cellular immune mechanisms and adenosine production by CD39 expressed by T regulatory cells impact xenogeneic tolerance mechanisms (with models developed in Project 3); and #2: Demonstrate therapeutic potential of transgenic upregulation of human CD39 and thrombomodulin in GalT-KO swine in thymokidney xenotransplant and tolerance models (in Projects 1 and 2). These strategies will include optimal immunosuppressive interventions with protocols to attempt induction of tolerance and ameliorate vascular inflammation in baboons. The overall goals of this application will be to effectively manage immune reactions, graft vascular Injury and thrombosis, currently associated with GalT-KO pig-to-baboon thymokidney xenotransplantation, and thereby provide clinically relevant survival times.