Preclinical Studies in Xenotransplantation

许多患有心脏或肾脏疾病等器官衰竭的人需要移植才能存活下来。在肾衰竭的情况下，患者可以通过人工肾维持生命，但这种机械治疗远不如移植令人满意。不幸的是，由于活体或身体捐献者的短缺，大多数将从移植中受益的患者无法接受一次移植。解决移植器官短缺的一个可能的办法是使用动物器官。猪是最合适的动物供体。然而，由于物种之间的距离，猪到人的器官立即被排斥。在过去的10年里，我们和其他人一直在试图了解哪些基因差异是重要的。现在很明显，有几个重要的区别。其中之一是猪体内的一种类似血型的分子，人类在移植时会立即与之发生反应。这就是半乳糖分子。我们和其他人已经成功地移除了制造这种分子的猪基因。此外，我们在猪身上添加了几个人类基因，以防止通常发生的早期强烈排斥反应。这些转基因猪的器官已经通过移植到狒狒和猴子身上进行了测试。移植过去在几分钟内就会被拒绝，现在可以存活几个月。然而，它们的器官仍然被导致移植器官凝结的过程排斥。我们现在了解了这一机制，并正在用人类基因来培育转基因猪，这些基因可以调节人类血液的凝结。该项目将通过将这些猪的器官移植到狒狒身上来测试它们的器官。我们还将制造一种特殊的猪品种，在其中组装所有这些基因改造。这包括移除一个猪基因和增加4到5个人类基因。我们认为，这种基因修改的组合极有可能使这种猪更适合作为器官捐赠者。

Many people with organ failure such as heart or kidney disease need a transplant to survive. In the case of kidney failure patients can be kept alive by the artificial kidney however this sort of mechanical traeatment is much less satisfactory than a transplant. Unfortunately most patients who would benefit from a transplant are unable to receive one beacuse of the shortage of living or cadaver donors. A possible solution to this shortage of organs for transplantation is to use animal organs. Pigs are the most suitable animal donor. However, a pig-to-human organ is rejected immediatly because of the distance between the species. Over the last 10 years, we and others have been trying to understand which genetic differences are important. It is now clear that there are several important differences. One of these is a Blood Group like molecule in the pig that humans react with immediatly on transplantation. This is called the Gal molecule. We and others have been successful in removing the pig gene that makes this molecule. In addition we have added several human genes to pigs to prevent the early vigorous rejection which usually occurs. Organs from these genetically modified pigs have been tested by transplantation into baboons and monkeys. The transplants which used to be rejected within minutes, now survive for months. However, they organs are still rejected by a process which causes clotting in the transplanted organs. We now understand the mechanism andare making genetically modified pigs with human genes which regulate clotting of human blood. This project will test organs from these pigs by transplantation into baboons. We will also make a special strain of pigs in which all these genetic modifications are assembled. This involves the removal of one pig gene and the addition of 4 or 5 human genes. We think it is highly likely that this combination of genetic modifications will make this strain of pigs much more suitable as organ donors.