XENOGENEIC NATURAL ANTIBODY TARGETS--STRUCTURE/FUNCTION

描述：（改编自申请人的摘要）移植是 慢性肾衰竭和有时急性肾衰竭的优选疗法， 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的限制，不如说是受到 捐助者。 因此，只有不到一半的人需要器官移植， 接受移植的人必须等待数月， 有时需要几年才能得到器官 这个问题可以克服，如果 用动物器官代替人的器官，一般首选猪 器官移植。 然而，临床异种移植， 是通过非常迅速和严重的排斥反应来防止的， 在数小时至数天内进行移植。 最近的研究表明，最严重的异种移植物 拒绝是由两个因素引起的。 一个是自然的反应 受体的抗体与供体器官中的抗原结合，激活受体的抗体。 补体系统 另一个因素是补体的不相容性 供体器官的调节蛋白与供体器官的补体系统 接受者，使异种器官非常容易在无意中 补体损伤。 第二个问题已经被解决了， 转基因猪的开发，表达人补体调节 proteins. 异种反应性抗体和抗原带来的问题 他们认为是本申请的主题。 总体目标 首先要确定真正的猪 人异种抗原识别的内皮细胞抗原 抗体和通过暴露于异种器官引起的抗体，以及 确定抗体-抗原相互作用的规则。 基于强 天然抗体识别的主要表位是 碳水化合物，Gala 1 -3Gal，提出了几种策略， 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 抗体及其在内皮细胞上的相应靶点将被 阐明。 这些研究将集中在混凝剂的性能， 内皮细胞和补体引起的结构和功能的变化。 处理异常生理的治疗方法将是 研究了

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.