Intravascular coagulopathy in discordant xenotransplantation

对于许多相关器官完全和不可逆转地衰竭的情况，成功的治疗方法是用一个新的器官替换那个器官。进行移植手术。众所周知，可供移植的器官远远少于所需的数量。这意味着对于那些有支持性治疗的情况，例如。人工肾，患者必须通过这种方法维持，然而对于其他器官，如心脏，肺和肝脏，没有机械的替代品。如果这些患者不接受移植，他们就会死亡。解决这个问题的一个办法是使用动物的器官。这被称为异种移植。猪是最合适的供体，尽管与人类有许多相似之处，但在将异种移植用于临床之前，仍有许多差异需要克服。这些差异是在非常精细的分子水平上的，并阻止器官正常整合到新的接受者中。其结果是，新的器官在几分钟内就会被排斥。这一过程被称为超急性排斥反应，通过对其机制的研究发现，这只是由于一些差异。我们和其他人已经对猪进行了基因改造，使它们具有人类基因，这完全防止了这种形式的排斥。然而，我们发现了第二个障碍，它会在几天后引起拒绝反应。现在已经知道，第二个障碍的主要原因是凝血系统中的一些差异。我们建议进行进一步的基因修改，我们认为这将防止这种排斥反应。该项目建议先检查各种基因修改，并在小动物模型中测试它们的效果，然后再制造和测试已插入人类基因的猪。如果我们成功了，用动物器官取代失败的人体器官的可能性将更近一步。

The successful treatment of many conditions in which the relevant organ has failed completely and irreversibly, is to replace that organ with a new one ie. to perform a transplant. It is well known that there are far fewer organs available for transplantation than the number needed. This means that for those conditions where a supportive treatment is available, eg. the artificial kidney, patients must be maintained by that method, however for other organs such as hearts, lungs and livers, there is no mechanical substitute. If these patients do not receive a transplant, they die. A solution to this problem is to use organs from animals. This is called xenotransplantation. The pig is the most suitable donor, however despite many similarities to humans which make it suitable, there are many differences which are still to be overcome before we can use xenotransplants clinically. These differences are at a very fine molecular level and prevent the normal integration of the organ into the new recipient. The result is that the new organ is rejected within minutes. This process is called hyperacute rejection and by research into its mechanism it was found to be due to just a few differences. We and others have genetically modified pigs so that they have the human genes and this has completely prevented this form of rejection. However,we have found a second barrier which causes a rejection response after a few days. It is now known that a major component of the cause of this second barrier is a few differences in the clotting system. We propose to make further genetic modifications which we think will prevent this rejection. This project proposes to examine various genetic modifications and test their effect in small animal models before going on to make and test pigs into which human genes have been inserted. If we are successful, the possibility of replacing failed human organs with animal organs will be a step closer.