XENOGENEIC NATURAL ANTIBODY TARGETS--STRUCTURE-FUNCTION

移植领域的一个主要挑战是关键 供体器官短缺。虽然异种移植可能会解决这个问题 问题是，超急性排斥反应限制了它的潜在应用。 器官移植时不可避免地发生的反应 在系统发育上相距遥远的物种。异种移植超急性排斥反应 以血管损伤的突出证据为特征的 由天然抗体和补体的反应引发 具有供体血管内皮衬的受者 管风琴。拟议研究的总体目标是澄清 异种移植超急性排斥反应的发病机制及研究进展 预防它的战略；这些目标的实现将有助于 异种移植在改善我国疾病中的应用 人类。 拟议研究的一个具体目标是进一步描述 一种猪内皮细胞糖蛋白gp135，它似乎是 人类天然抗体启动中最重要的靶点 排斥性反应。针对该病毒的单抗 将使用糖蛋白和/或部分氨基酸序列来分离 并克隆了全长cDNA.将使用蛋白质和cdna序列。 根据与其他已知基因的同源性推断gp135的功能 序列及其与超急性发作的病理生理学的关系 拒绝。以至于其他猪内皮细胞 糖蛋白被发现在病理生理上很重要，这些 糖蛋白也将被研究。 这个项目的另一个目标是定义人类自然的角色 抗体和补体在介导异种血管内皮损伤中的作用 人天然抗体、人和鼠单抗 针对特定的猪内皮细胞抗原，包括 Gp135，将在有和没有补充的情况下进行测试，以了解 刺激或“激活”猪内皮细胞。的表现形式 内皮细胞的激活在发生时将与特定的 抗内皮细胞抗体识别的结构和活性 作为刺激所需的补充部分或其组合。

One major challenge in the field of transplantation is the critical shortage of donor organs. While xenotransplantation might address this problem, its potential use is limited by the hyperacute rejection reaction that inevitably occurs when organs are transplanted between phylogenetically distant species. Hyperacute xenograft rejection is characterized by prominent evidence of vascular injury that is thought to be initiated by the reaction of natural antibodies and complement of the recipient with the endothelial lining of blood vessels of the donor organ. It is the overall objective of the proposed research to elucidate the pathogenesis of hyperacute xenograft rejection and to develop strategies to prevent it; the achievement of these goals will contribute to the application of xenotransplantation for amelioration of disease in humans. One specific aim of the proposed research is the further characterization of a porcine endothelial cell glycoprotein, gp135, which appears to be the most important target of human natural antibodies in the initiation of the rejection reaction. Monoclonal antibodies directed against this glycoprotein and/or partial amino acid sequences will be used to isolate and clone full length cDNA. The protein and cDNA sequences will be used to deduce the function of gp135 based on homology with other known sequences and as it relates to the pathophysiology of hyperacute rejection. To the extent that other porcine endothelial cell glycoproteins are found to be pathophysiologically important, these glycoproteins will be investigated as well. Another aim of this project is to define the roles of human natural antibodies and complement in mediating injury to xenogeneic endothelium. Human natural antibodies and human and murine monoclonal antibodies directed against specific porcine endothelial cell antigens, including gp135, will be tested with and without complement for the ability to stimulate or "activate" porcine endothelial cells. The manifestations of endothelial cell activation as it occurs will be related to the specific structures recognized by anti-endothelial cell antibodies and the active complement moieties or combination thereof required as a stimulus.