Thromboregulatory Barriers to Xenotransplantation

异种移植的血栓调节障碍

• 批准号: 8190128
• 负责人: SIMON C. ROBSON
• 金额: $ 32.77万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190128
• 关键词: 5' -Nucleotidase; Acute; Address; Adenosine; Antibodies; Anticoagulants; Antigens; Binding; Biological Response Modifiers; Blood Coagulation Disorders; Blood Coagulation Factor; Blood Platelets; Blood Vessels; Bone Marrow; Cations; Cells; Chimerism; Clinical Research; Coagulation Process; Consumption; Development; Disease; Endothelium; Enzymes; Excision; Failure; Family suidae; Functional disorder; G-Protein-Coupled Receptors; Generations; Goals; Graft Rejection; Graft Survival; Human; Immune; Immune response; Immunosuppressive Agents; Inbreeding; Inflammation Mediators; Inflammatory; Injury; Intervention; Islet Cell; Link; Mediating; Mediator of activation protein; Modeling; Molecular; Natural Immunity; Nucleosides; Nucleotides; Organ; Organ Transplantation; P2X-receptor; Papio; Pathway interactions; Pattern; Platelet Activation; Process; Production; Property; Protocols documentation; Purinergic P1 Receptors; Reaction; Regulation; Regulatory T-Lymphocyte; Research; Role; Signal Pathway; Signal Transduction; Stress; T-Cell Activation; Testing; Therapeutic; Thrombocytopenia; Thrombomodulin; Thrombosis; Time; Transgenic Organisms; Up-Regulation; Vascular Endothelium; Vascular Graft; Xeno; Xenograft procedure; adaptive immunity; bone; clinical application; clinically relevant; ectoADPase; ectoATPase; extracellular; heart xenograft; insight; kidney xenograft; novel; response; success; vascular inflammation

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.

只有当异种移植物丢失和排斥机制消失后，异种移植才会在临床上变得可行 更好地理解。去除优势基因的自交小型 GalT-KO 猪的开发 异种抗原是一个重大进步。然而，产生混合异种的问题仍然存在 狒狒嵌合并获得对异种细胞和血管化异种移植物的耐受性。 猪骨髓来源细胞的炎症反应与器官移植物的脉管系统有关 异常的免疫反应，以及促凝血激活和异种移植物的发育 微血管损伤。出现血栓形成过程和进行性异种移植微血管病 功能失调的免疫反应和已经记录的内在分子会加剧这种情况 不一致物种之间血栓调节的不相容性。我们在以下方面取得了重大进展 与 CD39 相关功能不相容相关的消耗性凝血病的定义机制 和跨物种的血栓调节蛋白，并通过确定与损伤相关的新血管标志物 体液排斥。我们最近表明 CD39 由内皮细胞和 T 细胞表达 调节细胞。因此，这种核酸外切酶产生的腺苷会阻止血小板活化，从而阻碍 凝血，也可作为免疫抑制介质。 我们的新研究将以这些成功和见解为基础，以实现以下具体目标：#1： 研究T细胞表达的CD39如何调节细胞免疫机制和腺苷生产 细胞影响异种耐受机制（使用项目 3 中开发的模型）； #2：展示 人 CD39 和血栓调节蛋白转基因上调 GalT-KO 猪的治疗潜力 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的免疫抑制干预措施以及尝试诱导的方案 狒狒的耐受性并改善血管炎症。该应用程序的总体目标是 有效管理目前与 GalT-KO 相关的免疫反应、移植血管损伤和血栓形成 猪到狒狒胸腺肾异种移植，从而提供临床相关的存活时间。