Innate Cellular Lectin-Mediated Binding of Xenogeneic Antigens

描述(由申请人提供)： 器官移植改变了数十万患者的生活。事实上，正是移植的成功导致了它的主要限制--根本没有足够的器官来满足需求。因此，研究人员正在寻找移植器官的替代来源。一种被认为可能成功的策略是使用动物器官取代失败的人体器官，这一过程被称为异种移植。基因工程和克隆技术的最新发展提高了人们的希望，即异种移植将在未来几十年内成为一种成功的治疗方法。猪是被认为是这方面最合适的器官来源的动物。体外肝脏灌流(ECLP)被认为是带血管的猪器官治疗患者的首批应用之一。ECLP被认为是合理的首选，因为暴发性肝功能衰竭患者有危及生命的情况，并且没有替代的临时支持手段。此外，ECLP可以在灵长类动物模型中实现血管器官的长期存活之前使用，因为ECLP已被证明在短时间内提供肝脏支持，这完全在目前灵长类动物血管猪器官的预期存活范围内。阻碍ECLP应用的障碍之一是当人类血液灌流猪肝脏时发生的红细胞损失。进一步的研究表明，猪Kupffer细胞通过Kupffer细胞表面蛋白受体识别外源糖类分子来破坏人的红细胞。这种糖识别蛋白质被称为凝集素。唾液酸已被确认为碳水化合物配体的一种成分，猪膜联蛋白I、II和IV已被确定为负责结合的潜在凝集素受体。特定的目标1和2建议确定被识别的确切糖，并评估猪膜联蛋白作为负责与人红细胞结合的受体的作用。特殊目的3建议利用这一新信息设计一种物质，以防止在肝脏异种灌流过程中人体红细胞的损失，并在体外猪肝灌流的临床前模型中测试这种物质。这项工作将促进我们对巨噬细胞识别来自其他物种的外来糖的理解，并使ECLP成为治疗暴发性肝功能衰竭的更有用的工具。

DESCRIPTION (provided by applicant): Organ transplantation has changed the lives of hundreds of thousands of patients. In fact, it is the success of transplantation that has led to its major limitation-there simply are not enough organs to meet the demand. Thus, researchers are looking for alternative sources of organs for transplantation. A strategy thought likely to succeed is the use of animal organs to replace failed human organs, a process known as xenotransplantation. Recent developments in genetic engineering and cloning technology have raised hopes that xenotransplantation will become a successful treatment within the next few decades. The pig is the animal felt to be the most appropriate source of organs in this regard. Extracorporeal liver perfusion (ECLP) has been suggested as one of the first applications of a vascularized porcine organ for the treatment of a patient. ECLP is felt to be a reasonable first choice because patients in fulminant liver failure have a lifethreatening condition and do not have alternative temporary means of support. In addition, ECLP could be used before long-term survival of vascularized organs has been achieved in a primate model as ECLP has been shown to provide hepatic support over a short period of time that is well within the current expected survival of vascularized porcine organs in primates. One of the barriers preventing the application of ECLP is the loss of erythrocytes that occurs when human blood perfuses a porcine liver. Further investigation has demonstrated that porcine Kupffer cells are responsible for the destruction of the human erythrocytes by a mechanism involving Kupffer cell surface protein receptor recognition of foreign human sugar molecules. Such sugar recognizing proteins are called lectins. Sialic acid has been identified as a component of the carbohydrate ligand being recognized and porcine annexins I, II and IV have been identified as potential lectin receptors responsible for the binding. Specific aims 1 and 2 propose to identify the exact sugars being recognized and to evaluate the role of porcine annexins as the receptor responsible for binding human erythrocytes. Specific aim 3 proposes to use this new information to design a substance that will prevent the loss of human erythrocytes during liver xenoperfusion and to test this substance in a pre-clinical model of extracorporeal porcine liver perfusion. This work will advance our understanding of macrophage recognition of foreign sugars from other species and make ECLP a more useful tool in treating fulminant hepatic failure.