THROMBOREGULATORY BARRIERS TO XENOTRANSPLANTATION

异种移植的血栓调节障碍

• 批准号: 6649916
• 负责人: SIMON C. ROBSON
• 金额: $ 29.62万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6649916
• 关键词: anticoagulants; antifibrinolytic agents; baboons; bone marrow transplantation; disseminated intravascular coagulation; fibrinolysis; gene therapy; heart transplantation; immune tolerance /unresponsiveness; kidney transplantation; laboratory mouse; laboratory rat; miniature swine; plasminogen activator inhibitors; protein C; thromboplastin; thrombosis; transplant rejection; von Willebrand factor; xenotransplantation

Xenotransplantation may become a clinical reality once we more fully understand the mechanisms of rejection and can consistently obtain xenograft survival without systemic toxicity. Although hyperacute rejection can now be abrogated, vascularized xenografts are still subject to acute vascular rejection, alternatively referred to as delayed xenograft rejection. This latter mode of rejection is associated with vascular-based inflammation, thrombocytopenia and the consumption of coagulation factors that may evolve to disseminated intravascular coagulation (DIC). In addition, cellular xenotransplantation procedures to induce tolerance by mixed chimerism are associated with widespread thrombotic vascular injury. The mechanisms underlying DIC and thrombotic microangiopathy in these settings are unclear. The mechanisms underlying DIC and thrombotic microangiopathy in these settings are unclear. Low levels of inflammatory mediators within vascularized xenografts, or potentially within the recipient vasculature after the infusion of xenogeneic cells, could promote vascular thrombosis. Molecular incompatibilities can also be shown between primate coagulation factors e.g. thrombin, and natural anti-coagulants e.g. thrombomodulin on xenogeneic leukocytes and endothelium We plan to identify and further characterize mechanisms underlying the development of coagulation disturbances and thrombotic responses in primates, temporally related to the transplantation of vascularized xenografts and/or infusion of xenogeneic cells from swine. Initially, xenoreactive antibody mediated pro-coagulant responses in the absence of complement will be defined in vitro and then studied in vivo. We will also demonstrate how xenogeneic cells cause platelet-aggregate formation. Molecular barriers relating to excessive thrombin generation, heightened platelet interactions with porcine sub-endothelial matrix associated von Willebrand factor the potential failure to regulate fibrinolysis will be then investigated in depth. Our data should indicate suitable pharmacological measures and gene therapeutic modalities for the control of thrombotic complications associated with organ and cellular xenotransplantation. This approach should establish whether disordered regulation of coagulation between discordant species will present yet another barrier to xenograft survival. Control of vascular inflammation and thrombosis should also promote establishment of mixed xenogeneic chimerism; to facilitate rigorous testing of mechanisms of immunological tolerance to vascularized xenografts. These studies will be judged successful if novel and clinically relevant pharmacological and genetic anti-thrombotic strategies develop from our future experimental observations.

一旦我们更充分地了解排斥反应的机制，并且能够持续地获得无全身毒性的异种移植存活，异种移植可能成为临床现实。虽然超急性排斥现在可以废除，血管化异种移植物仍然受到急性血管排斥，或者被称为延迟异种移植物排斥。后一种排斥反应模式与基于血管的炎症、血小板减少和凝血因子的消耗有关，这些因素可能演变为弥散性血管内凝血（DIC）。此外，通过混合嵌合诱导耐受性的细胞异种移植程序与广泛的血栓性血管损伤有关。在这些情况下DIC和血栓性微血管病变的机制尚不清楚。在这些情况下DIC和血栓性微血管病变的机制尚不清楚。输注异种细胞后，带有血管的异种移植物内或受体血管内低水平的炎症介质可促进血管血栓形成。灵长类动物凝血因子（如凝血酶）和天然抗凝剂（如凝血调节素）在异种白细胞和内皮上的分子不相容也可以被证明。我们计划确定并进一步表征灵长类动物凝血障碍和血栓反应发展的机制，这些机制暂时与血管化异种移植物移植和/或猪异种细胞输注有关。首先，在没有补体的情况下，异种反应性抗体介导的促凝反应将在体外定义，然后在体内研究。我们还将演示异种细胞如何引起血小板聚集形成。与凝血酶生成过多、血小板与猪内皮下基质相关的血管性血友病因子相互作用增强以及调节纤维蛋白溶解的潜在失败相关的分子障碍将被深入研究。我们的数据应该表明适当的药理学措施和基因治疗方式来控制与器官和细胞异种移植相关的血栓性并发症。这种方法应该确定不和谐种之间的凝血调节紊乱是否会成为异种移植物存活的另一个障碍。控制血管炎症和血栓形成也应促进混合异种嵌合的建立；促进对血管化异种移植物免疫耐受机制的严格测试。如果从我们未来的实验观察中发展出新的和临床相关的药理学和遗传抗血栓策略，这些研究将被认为是成功的。