THE ROLE OF COMPLEMENT IN XENOTRANSPLANTATION

补体在异种移植中的作用

• 批准号: 6110254
• 负责人: Michael M Frank
• 金额: --
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6110254
• 关键词: Macaca fascicularis; SDS polyacrylamide gel electrophoresis; baboons; calcium flux; cell cell interaction; cell cycle; complement; complement inhibitors; complement pathway; cytokine; high performance liquid chromatography; immunoglobulin G; inositol phosphates; monoclonal antibody; protein purification; swine; transplant rejection; vascular endothelium; xenotransplantation

The overall objective is to elucidate the role of complement in the pathogenesis of xenograft rejection. It is well established that complement activation plays a key role in hyperacute xenograft rejection and its believed that the mechanism of damage of pig xenograft in primates is mediated by natural antibody and the classical complement pathway. Xenografts that survive hyperacute rejection may be destroyed some days later by a process termed acute vascular rejection. The histology of acute vascular rejection is identical to that of hyperacute rejection and we hypothesize that cobra venom factor does not complement components activated by the CVF in small amounts to the graft. This project uses novel complement inhibition and inactivation to prevent complement binding to graft endothelium, studies the effect of complement binding in endothelial cell activation, and examines the binding of immunologically active materials to the graft in such a way as to inhibit or delay acute vascular rejection. These experiments represent an approach to acute vascular rejection using more extensive complement inhibition incorporating agents which activate and inhibit complement. The second aim is to elucidate the mechanism by which antibody and complement binding to grafts initiate graft rejection. The effect of binding of complement proteins to endothelial monolayers and generation of complement activation products will be examined. Cytokine production will be monitored as to explore how complement binding and endothelial cell activation proceed. Finally, the process of accommodation will be examined. The interaction of grafts with antibody and complement under some circumstances appears to protect graft from further damage in several experimental models. The mechanism of this effect will be explored with particular emphasis on the binding of complement degradation fragments to critical graft sits in such a way that the binding of further active complement products is inhibited.

总体目标是阐明补体在体内的作用。 异种移植排斥反应的发病机制。众所周知， 补体激活在异种移植超急性排斥反应中的关键作用 并认为猪异种移植损伤的机制可能是 灵长类是由天然抗体和经典补体介导的 路径。存活超急性排斥反应的异种移植物可能被摧毁 几天后，发生了一种称为急性血管排斥反应的过程。这个 急性血管性排斥的组织学特征与超急性相同 排斥反应，我们假设眼镜蛇毒液因子不能补充 由CVF激活的少量成分被移植到移植物。这 Project使用新的补体抑制和失活来预防 补体与移植物内皮结合，研究补体的作用 结合在内皮细胞激活，并检查结合 免疫活性物质对移植物的抑制作用 或延缓急性血管排斥反应。这些实验代表了一种 应用更广泛补体治疗急性血管排斥反应的探讨 加入激活和抑制补体的试剂的抑制作用。 第二个目的是阐明抗体和 补体与移植物结合可引发移植物排斥反应。的影响 补体蛋白与血管内皮细胞单层的结合及生成 补体激活产物的数量将被检查。细胞因子的产生 将被监测以探索补体结合和内皮细胞如何 细胞激活继续进行。最后，通融的过程将是 检查过了。移植物与抗体、补体的相互作用 在某些情况下，似乎可以保护贪污不受进一步损害 几个实验模型。这种效应的机制将是 重点探讨补语的约束性 降解碎片到关键移植物的方式是这样的 进一步的活性补体产物的结合被抑制。