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.

一旦异种移植机制丢失和排斥，异种移植只会在临床上可行 更好地理解。近交微型galt-ko猪的发展，取消了主要的 Xeno-Antigen一直是一个重大进步。但是，问题仍然存在于产生混合异种 狒狒的嵌合体并获得对异种细胞和血管化异种移植的耐受性。 对猪骨髓衍生细胞和器官移植的脉管系统的炎症反应与 与异常的免疫反应以及proc凝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微病变出现 通过功能失调的免疫反应加剧，已经记录了固有的分子 不一致的物种之间的血小板调节不兼容。我们在 与CD39相关功能不兼容相关的消费凝血病的定义机制 以及通过确定与 体液拒绝。我们最近表明，CD39由内皮表达，也是T 调节细胞。因此，该核核苷酸酶产生的腺苷阻碍了血小板激活阻碍 凝血，还用作免疫抑制介质。 我们的新研究将以这些成功和见解为基础，以解决以下特定目标：＃1： 研究如何通过T调节表达的CD39的细胞免疫机制和腺苷的产生 细胞影响异构耐受性机制（在项目3中开发的模型）；和＃2：演示 人CD39的转基因上调和在Galt-ko猪中的治疗潜力 胸腺自然移植和耐受模型（在项目1和2中）。 这些策略将包括最佳的免疫抑制干预措施，以尝试归纳 狒狒的耐受性和改善血管炎症。该应用程序的总体目标将是 有效管理与Galt-KO有关的免疫反应，移植血管损伤和血栓形成 猪至巴博尼的胸腺异体异种移植，从而提供临床相关的生存时间。