BARRIER TO XENOTRANSPLANTATION

本申请提出了旨在阐明 异种心脏移植免疫屏障的研究进展 克服这一障碍的策略。 这一努力的理由是， 是人类器官的严重短缺 同种异体移植 免疫障碍包括超急性 未修饰受体的排斥反应和未修饰受体的急性血管性排斥反应。 异种移植物接受者是未经修饰的接受者和急性 异种移植物接受者的血管排斥反应， 抗供体抗体和/或补体。 其他障碍包括贪污 中性粒细胞、自然杀伤细胞和淋巴细胞介导的损伤。 该计划使用了一个临床前模型，涉及移植 猪心植入食蟹猴体内。 的贡献 天然抗体、补体和炎症的排斥过程 细胞以及再灌注损伤，将得到解决。 一个中央 该计划的主题集中在内皮细胞作为氧化剂的目标 损伤以及作为效应系统的体液和细胞介导的应答。 另一个中心主题集中在血管化的获得性抵抗， 器官移植到体液介导的损伤;测试可能 为这个“被接纳”的国家做出贡献。 项目1认为， 氧化剂介导的损伤对体液介导的排斥反应的贡献。 项目2考虑了天然抗体的作用，项目3 考虑了补体在这一过程中的作用。 项目4调查 内皮细胞对体液损伤的反应。 项目5探索 中性粒细胞在急性血管排斥反应中的作用 项目6和 7研究自然杀伤细胞和T淋巴细胞如何分别 可能会与异种器官发生反应 项目8研究 体液性排斥反应的发病机制和潜在的治疗 动物模型 该计划的整体努力得到了一个 管理核心和细胞培养和免疫病理学核心。

This application proposes a programmatic effort aimed at elucidating the immunological barrier to cardiac xenotransplantation and the development of strategies to overcome that barrier. The rationale for this effort is a very critical shortage of human organs available for allotransplantation. The immunological hurdles include hyperacute rejection in unmodified recipients and acute vascular rejection in xenograft recipients who have been unmodified recipients and acute vascular rejection in xenograft recipients who have been depleted of anti-donor antibodies and/or complement. Other hurdles involve graft injury mediated by neutrophils, natural killer cells and lymphocytes. The program uses a preclinical model involving the transplantation of porcine hearts into the cynomolgus monkeys. The contribution to the rejection process of natural antibodies, complement, and inflammatory cells as well as of reperfusion injury, will be addressed. One central theme of the program focuses on endothelial cells as a target of oxidant injury and in humoral and cell mediated responses as an effector system. Another central theme focuses on the acquired resistance of vascularized organ grafts to humoral mediated injury; test the mechanisms which may contribute to this "accommodated" state. Project 1 considers the contribution of oxidant mediated injury of humoral mediated rejection. Project 2 considers the role of natural antibodies and Project 3 considers the role of complement in this process. Project 4 investigates endothelial cell responses to humoral injury. Project 5 explores the contribution of neutrophils to acute vascular rejection. Projects 6 and 7 investigate how natural killer cells and T-lymphocytes, respectively might interact with a xenogeneic organ. Project 8 studies the pathogenesis and potential treatment of humoral rejection in the large animal model. The overall effort of the program is supported by an administrative core and a cell culture and immunopathology core.