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BARRIER TO XENOTRANSPLANTATION

异种移植的障碍

基本信息

批准号：
2655251
负责人：
Michael M Frank
金额：
$ 118.18万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-02-01 至 1999-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2655251
关键词：
transplant rejection xenotransplantation

项目摘要

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.

本申请提出了一项旨在阐明心脏异种移植的免疫屏障及其发展克服这一障碍的策略。这项努力的理由可用于人体器官的严重短缺同种异体移植。免疫学障碍包括超急性未改良受体的排斥反应和急性血管排斥反应未经修饰的异种移植受者和急性受者已耗尽异种移植受者的血管排斥抗供体抗体和/或补体。其他障碍涉及贪污由中性粒细胞、自然杀伤细胞和淋巴细胞介导的损伤。该计划使用涉及移植的临床前模型将猪心脏植入食蟹猴体内。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的问题将得到解决。一中央该计划的主题侧重于作为氧化剂目标的内皮细胞损伤以及作为效应系统的体液和细胞介导的反应。另一个中心主题集中于血管化的获得性抵抗力器官移植导致体液介导的损伤；测试可能的机制有助于这种“适应”状态。项目 1 考虑氧化剂介导的损伤对体液介导的排斥反应的贡献。项目 2 考虑天然抗体的作用，项目 3 考虑补体在此过程中的作用。项目 4 调查内皮细胞对体液损伤的反应。项目 5 探索中性粒细胞对急性血管排斥反应的贡献。项目 6 和 7 分别研究自然杀伤细胞和 T 淋巴细胞如何可能与异种器官相互作用。项目 8 研究大型体液排斥的发病机制和潜在治疗动物模型。该计划的总体努力得到了支持行政核心以及细胞培养和免疫病理学核心。