Coagulation Control To Protect Gaitko Lung and Liver Xenografts

凝血控制保护 Gaitko 肺和肝异种移植物

• 批准号: 8009659
• 负责人: Richard N Pierson
• 金额: $ 72.68万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8009659
• 关键词: Address; Adhesions; Adsorption; Antibodies; Anticoagulants; Attenuated; Avidity; Binding; Blood; Blood Coagulation Disorders; Blood Platelets; Blood Vessels; CD46 Antigen; Clinical; Clinical Trials; Coagulation Process; Complement; Complement Activation; Complement component C1s; DDAVP; Data; Disease; Endothelium; Engineering; Evaluation; Excision; Failure; Family suidae; Fibrin; Filtration; Glycoproteins; Goals; Heart; Hemorrhage; Hepatic; Hour; Human; Immunity; Immunosuppression; In Vitro; Inflammatory; Injury; Intervention; Kidney; Knowledge; Lepirudin; Life; Link; Liver; Lung; Mediating; Membrane Glycoproteins; Modeling; Molecular; Molecular Target; Neuraminidase; Organ; Organ Transplantation; Papio; Pathogenesis; Pathway interactions; Performance; Perfusion; Physiological; Plasma; Primates; Protein C; Proteins; Publishing; Reagent; Regimen; Relative (related person); Resources; Respiratory physiology; Role; Sepsis; Sialic Acids; Structure; Testing; Thrombin; Thrombocytopenia; Thrombomodulin; Thrombosis; Transplantation; VWF gene; Work; Xenograft procedure; activated Protein C; allotransplant; base; bivalirudin; clinical application; clinically relevant; complement pathway; ex vivo perfusion; experience; genetic regulatory protein; improved; inhibitor/antagonist; insight; kidney xenograft; liver transplantation; liver xenograft; lung injury; lung xenograft; neutrophil; novel; prevent; programs; receptor; success; sugar; thrombolysis; von Willebrand Factor; zanamivir

Hyperacute rejection ofthe heart and kidney is reliably prevented when GalTKO organs are used that additionally express a human complement pathway regulatory protein (hCPRP). In contrast, although GalTKO.hCPRP pig lung xenograft function is significantly prolonged relative to GalTKO or hCPRP lungs, lung injury nonetheless occurs within hours of transplantation into baboons or following perfusion with human blood. Similarly, platelet sequestration occurs almost immediately when GalTKO.hCPRP pig livers are orthotopically transplanted in baboons, and limits recipient survival. A number of molecular incompatibilities between pig endothelial membrane glycoproteins and primate platelet receptors and plasma coagulation pathway proteins probably explain the mechanistic basis of coagulation pathway dysregulation and platelet sequestration in lung and liver xenograft injury. These incompatibilities may also contribute to related problems in heart and kidney xenotransplants, thrombotic microangiopathy (TM) and consumptive coagulopathy (CC). In this Project we will take advantage ofthe GalTKO.hCPRP pig lung's particular avidity for platelet and neutrophil sequestration, and its propensity to amplify coagulation pathway activation. Using a combination of clinically available approaches to impact thromboregulation (DDAVP, to deplete donor vWF pretransplant; zanamivir, a sialydase inhibitor, to maintain sialic acid expression on circulating platelet receptors and associated vWF) and unique molecular targeting reagents (an anti-GPlB Fab and an antisialydase antibody), Aim 1 will test the hypothesis that GPlB/vWF, modulated by desialydation, mediate primate platelet and neutrophil sequestration by porcine endothelium. In Aim 2, GalTKO.hCPRP pig lungs that also express human thrombin pathway regulatory proteins (thrombomodulin or endothelial protein C receptor) will reveal whether molecular incompatibilities in this pathway contribute significantly to lung injury, and whether expression of these molecules is protective. Aim 3 will determine whether strategies arising from Aims 1 and 2 will consistently yield life-supporting function of a pig lung in a baboon, and whether a similar approach reliably prevents thrombocytopenia in a baboon supported by a GalTKO.hCPRP pig liver.

当使用GalTKO器官时， 另外表达人补体途径调节蛋白（hCPRP）。相比之下，虽然 GalTKO.hCPRP猪肺异种移植物功能相对于GalTKO或hCPRP肺显著延长， 然而，肺损伤发生在移植到狒狒体内的数小时内或灌注后， 人血类似地，当GalTKO.hCPRP猪肝脏中的GalTKO. 被原位移植到狒狒体内，限制了受体的存活。 猪内皮细胞膜糖蛋白与血管内皮细胞膜糖蛋白之间的一些分子不相容性 灵长类血小板受体和血浆凝血途径蛋白可能解释了 肺和肝异种移植物损伤中凝血途径失调和血小板隔离。这些 不相容性也可能导致心脏和肾脏异种移植中的相关问题，血栓形成 微血管病（TM）和消耗性凝血病（CC）。 在本项目中，我们将利用GalTKO.hCPRP猪肺对血小板的特殊亲合力 和中性粒细胞隔离，及其放大凝血途径激活的倾向。使用 临床上可用的影响血栓调节的方法的组合（DDAVP，以消耗供体vWF 移植前;扎那米韦，一种唾液酸酶抑制剂，用于维持循环血小板上唾液酸的表达 受体和相关的vWF）和独特的分子靶向试剂（抗GP 1B Fab和抗唾液酸酶 目的1将检验通过去唾液酸化调节的GP 1B/vWF介导 灵长类血小板和中性粒细胞被猪内皮隔离。在目标2中，GalTKO.hCPRP猪肺 其也表达人凝血酶途径调节蛋白（血栓调节蛋白或内皮蛋白C 受体）将揭示该途径中的分子不相容性是否对肺有显着影响 损伤，以及这些分子的表达是否具有保护性。目标3将决定战略是否 目标1和2所产生的肺功能将始终在狒狒体内产生猪肺的生命维持功能， 类似的方法是否可靠地预防了GalTKO.hCPRP支持的狒狒的血小板减少症 猪肝。