XENOGENEIC NATURAL ANTIBODY TARGETS--STRUCTURE/FUNCTION

描述：(改编自申请者的摘要)移植是 慢性和有时是急性肾功能衰竭的首选疗法， 心脏、肝脏和肺。移植的临床应用是 与其说是受到免疫介导的排斥反应的限制，不如说是受到 捐赠者。因此，实际上需要器官移植的人中只有不到一半 接受移植的人必须等上几个月， 有时需要数年时间才能接受器官移植。这个问题是可以克服的，如果 动物器官被用来代替人类，猪通常是首选的。 供移植的器官。然而，临床异种移植，因此， 是通过非常迅速和严重的排斥反应来防止的，这种反应破坏了 在几个小时到几天的时间里嫁接。 最近的研究表明，最严重的异种移植类型 拒绝是由两个因素引起的。其一是自然的反应 受体的抗体与供体器官中的抗原结合，激活 补充制。另一个因素是补体的不相容 供体器官的调节蛋白与补体系统 受体，使异种器官在不经意间高度易感 补体损伤。第二个问题已经被 表达人类补体调节基因的转基因猪的研制 蛋白质。异种反应性抗体和抗原引起的问题 他们认识到这是本申请的主题。总体目标 这项拟议的研究是第一次识别真正的猪 人异种反应性天然可识别的内皮细胞抗原 抗体和因暴露于异种器官而引起的抗体 确定管理抗体-抗原相互作用的规则。基于强大的 有证据表明，天然抗体识别的主要表位是 碳水化合物，Gala1-3Gal，提出了几种策略，它们将 从供体器官中消除这种碳水化合物的表达。第二, 异种反应性之间相互作用的生理后果 对内皮细胞的抗体及其相应的靶点将是 已澄清。这些研究将集中在凝聚剂的性能上 血管内皮细胞与补体引起的结构和功能变化。 处理异常生理的治疗方法将是 调查过了。

DESCRIPTION: (Adapted from the applicant's abstract) Transplantation is the preferred therapy for chronic and sometimes for acute failure of the kidney, heart, liver and lungs. The clinical application of transplantation is limited not so much by immune mediated rejection as it is by the number of donors. Thus, fewer than half of those who need organ transplants actually received them and those who do receive transplants must wait for months and sometimes years to receive an organ. This problem could be overcome if animal organs, the pig being generally preferred, were used in lieu of human organs for transplantation. However, clinical xenotransplantation, as such, is prevented by very rapid and severe rejection reactions that destroy the graft over a period of hours to days. Recent studies have revealed that the most severe types of xenografts rejection are initiated by two factors. One is the reaction of natural antibodies of the recipient with antigens in the donor organ, activating the complement system. The other factor is the incompatibility of complement regulatory proteins of the donor organ with the complement system of the recipient, rendering the xenogeneic organ highly susceptible in inadvertent injury by complement. The second problem has been overcome by the development of transgenic pigs, expressing human complement regulatory proteins. The problem posed by xenoreactive antibodies and the antigens they recognize is the subject of this application. The overall objectives of the proposed research are first to identify the actual porcine endothelial cell antigens recognized by human xenoreactive natural antibodies and the antibodies elicited by exposure to a xenogeneic organ and determine the rules governing antibody-antigen interaction. Based on strong evidence that the major epitope recognized by natural antibodies is a carbohydrate, Gala1-3Gal, several strategies are proposed which would eliminate the expression of that carbohydrate from a donor organ. Second, the physiologic consequences of the interaction between xenoreactive antibodies and their corresponding targets on endothelial cells will be elucidated. These studies will focus on the coagulant properties of endothelium and the changes in structure and function induced by complement. Therapeutic approaches to dealing with aberrant physiology will be investigated.