Sandrin M S, McKenzie I F
Molecular Immunogenetics Laboratory, Austin Research Institute, Austin Hospital, Heidelberg, Victoria, Australia.
Immunol Rev. 1994 Oct;141:169-90. doi: 10.1111/j.1600-065x.1994.tb00877.x.
The transplantation of pig organs to humans (xenotransplantation) is now receiving serious consideration because of the shortage of human donors for organ transplants of kidney, liver and heart, and of islet cell transplantation for diabetes. The problem with such xenografts would be hyperacute rejection--mediated by natural antibodies in humans to pig antigens, complement fixation to endothelial cells, and the rapid onset of intravascular coagulation. It is now clear that the major target of the natural IgM and IgG antibodies is the terminal carbohydrate epitope Gal alpha(1,3)Gal, formed by the alpha 1,3galactosyl transferase, which places a terminal galactose residue in an alpha-linkage to another galactose. The alpha 1,3galactosyl transferase in the pig gives rise to very high endothelial cell expression of Gal alpha(1,3)Gal, a ready explanation for the hyperacute rejection of vascularized organs. In addition the parenchuma of liver and kidneys have high levels of Gal alpha-(1,3)Gal. These tissues will all fail in a pig-to-human transplant in what can now be precisely defined in terms of antigen and antibody. We have already made some suggestions for removal of anti-Gal alpha(1,3)Gal antibodies and if the procedure were technically feasible xenotransplantation could be attempted now, especially in patients doomed to a certain death because of the absence of a donor (especially for liver where ex vivo perfusion could be performed). However, the immune system is far from simple, as is shown by the healthy status of mice lacking MHC Class I, Class II or both Class I & II molecules. Perhaps the curtain is about to go up to reveal a new scene! Islets differ from the other tissues and may well not undergo acute antibody-mediated hyperacute rejection--it will be of interest to see how these fare in xenotransplantation models or even in patients. Again, normal individuals do not have anti-islet antibodies; but a proportion of diabetic patients do have such antibodies--whether these will cause hyperacute or acute rejection or are markers of immunity of T-cell type, remains to be seen. Whatever, the area is exciting, is progressing rapidly and, as indicated elsewhere, within a few years we should know whether modified pig tissue can be grafted to some patients. The isolation of the cDNA clone encoding the pig alpha 1,3 galactosyl transferase is an essential first step in the production of a transgenic pig lacking the alpha 1,3Galactosyltransferase and therefore the Gal alpha(1,3)Gal epitope, and such animals could serve as donor for human transplantation.
由于肾脏、肝脏和心脏等器官移植以及糖尿病胰岛细胞移植的人类供体短缺，猪器官移植到人类（异种移植）目前正在得到认真考虑。这种异种移植的问题将是超急性排斥反应——由人类针对猪抗原的天然抗体介导，补体固定在内皮细胞上，并迅速引发血管内凝血。现在很清楚，天然IgM和IgG抗体的主要靶标是由α1,3半乳糖基转移酶形成的末端碳水化合物表位Galα(1,3)Gal，它将一个末端半乳糖残基以α键连接到另一个半乳糖上。猪体内的α1,3半乳糖基转移酶导致Galα(1,3)Gal在内皮细胞上高度表达，这为血管化器官的超急性排斥反应提供了一个现成的解释。此外，肝脏和肾脏的实质中Galα-(1,3)Gal水平也很高。在猪到人的移植中，这些组织都会失败，现在可以根据抗原和抗体精确界定这种情况。我们已经对去除抗Galα(1,3)Gal抗体提出了一些建议，如果该程序在技术上可行，现在就可以尝试异种移植，特别是对于因没有供体而注定死亡的患者（尤其是对于可以进行体外灌注的肝脏）。然而，免疫系统远非简单，缺乏MHC I类、II类或I类和II类分子的小鼠的健康状况就表明了这一点。也许帷幕即将拉开，展现出一个新的场景！胰岛与其他组织不同，很可能不会经历急性抗体介导的超急性排斥反应——看看它们在异种移植模型甚至患者中的表现将很有趣。同样，正常个体没有抗胰岛抗体；但一部分糖尿病患者确实有这种抗体——这些抗体是否会导致超急性或急性排斥反应，或者是否是T细胞类型免疫的标志物，还有待观察。无论如何，这个领域令人兴奋，发展迅速，正如在其他地方指出的，几年内我们应该会知道经过改造的猪组织是否可以移植给一些患者。分离编码猪α1,3半乳糖基转移酶的cDNA克隆是生产缺乏α1,3半乳糖基转移酶从而缺乏Galα(1,3)Gal表位的转基因猪的关键第一步，这样的动物可以作为人类移植的供体。
