Xenogeneic Natural Antibody Targets-Structure/Function

描述(申请人提供)：移植领域的主要问题是缺乏人体器官和组织供需要的人使用 他们。这个问题如此严重，据一些人估计，只有5%-15%的人 进行了所需的器官移植。克服这一问题的一种方法 问题是用动物器官代替人体器官进行移植， 这就是异种移植。而异种移植原则上可以解决 器官短缺的问题，目前还不可行，因为 受者的免疫系统会对移植物产生严重反应。第一 这种反应的表现是超急性排斥反应。由 异种反应性抗体的结合和补体的激活，超急性 现在可以通过各种方法克服排斥反应，包括使用猪 表达人类补体调节蛋白作为异种移植的来源。 当避免超急性排斥反应时，异种移植物会受到急性血管的影响。 拒绝。急性血管排斥反应在一段时间内破坏异种器官移植 几天到几周。它似乎是由接受者体内的抗体引起的， 与移植物中的血管结合导致内皮细胞激活和 随之而来的组织损伤。幸运的是，急性血管排斥不是 器官异种移植的不变结局。在某些情况下，例如当 异种反应性抗体暂时耗尽，移植物似乎会获得 对抗供体抗体损伤的抵抗力，这种情况称为 住宿。这项申请提出了一些研究，将阐明 引起心脏急性血管排斥的异种反应性抗体 并确定抗体或其他因子如何与移植物反应 可能会导致通融。研究将在一个模型系统中进行，其中 猪心被异位移植到狒狒体内。抗体 由狒狒对猪器官产生的反应将在 发生急性血管排斥或适应的时间。它的特殊性 在这些抗体中，抗原的数量和在猪中的频率将是 以及这些抗体或其他因素诱导的机制 血管内皮细胞的变化将被确定。这些实验将 提供对制定新的预防战略至关重要的信息 急性血管排斥或促进调节的发生 异种心脏移植。

DESCRIPTION (provided by applicant): The major problem in the field of transplantation is the lack of human organs and tissues for those who need them. This problem is so severe that by some estimates only 5-15 percent of the organ transplants needed is carried out. One approach to overcoming this problem is to use animal organs in lieu of human organs for transplantation, that is xenotransplantation. While xenotransplantation could in principle solve the problem of the shortage of organs, it is not presently feasible because the immune system of the recipient reacts severely with the graft. The first manifestation of this reaction is hyperacute rejection. Triggered by the binding of xenoreactive antibodies and the activation of complement, hyperacute rejection can now be overcome by various means including the use of pigs expressing human complement regulatory proteins as the source of xenografts. When hyperacute rejection is averted, a xenograft is subject to acute vascular rejection. Acute vascular rejection destroys organ xenografts over a period of days to weeks. It appears to be caused by antibodies in the recipient, which bind to blood vessels in the graft causing activation of endothelial cells and tissue injury that ensues. Fortunately, acute vascular rejection is not an invariable outcome of organ xenografts. Under some conditions, such as when xenoreactive antibodies are temporarily depleted, a graft may seemingly acquire resistance to injury by anti-donor antibodies, a condition referred to as accommodation. This application proposes studies that will elucidate the nature of the xenoreactive antibodies that cause acute vascular rejection of cardiac xenografts and determine how antibodies or other factors reacting with a graft may induce accommodation. Studies will be conducted in a model system in which porcine hearts are transplanted heterotopically into baboons. The antibodies produced by the baboons in response to the porcine organs will be studied at the time that acute vascular rejection or accommodation occurs. The specificity of those antibodies, number of antigens and frequency in pigs will be determined and the mechanisms by which those antibodies or other factors induce changes in endothelial cells will be ascertained. These experiments will provide information critical to the devising of new strategies for preventing acute vascular rejection or promoting the occurrence of accommodation of cardiac xenografts.