GalT-knockout pig to monkey xenogeneic kidney and islet transplantation

由于免疫抑制疗法的进步，器官移植在美国、欧洲和日本已经成为终末期器官衰竭的主要治疗方法。然而，目前供体器官短缺是一个严重的问题。一个有吸引力的解决方案是利用微型猪供体器官进行异种移植。然而，由于人血液中含有针对组成性表达的猪细胞表面碳水化合物半乳糖- α -1,3-半乳糖（Gal）的天然抗体（NAb），猪到人异种移植最初会导致超急性（移植物在1天内丢失）体液排斥反应。在过去的四年里，在这笔赠款的支持下，我们取得了两项重大成就，这两项成就以前在日本都没有取得过。成果1（国内首次成功）：利用从哈佛医学院TBRC获得的GalT-KO微型猪体细胞核的核移植，我们和我们的同事通过合作努力，成功地生产了更多的GalT-KO微型猪。然后，我们将这些猪的GalT-KO肾脏移植到猴体内，以证实超急性排斥反应是可以避免的。异种移植后15天内未发生排斥反应。成果2（国内首次成功）：我们成功地从小型猪身上分离出胰岛，并将这些胰岛异种移植后，我们观察到猴子的正常血糖水平维持了两个月。此外，我们还探讨了异种移植排斥反应的机制。特别是，我们使用GalT-KO猪的结果表明CD59参与了调节的发展。此外，我们的研究表明：(1)转基因人CD47对猪细胞和(2)可溶性血栓调节素或肝细胞生长因子的免疫调节/保护作用。在这项资助的支持下，我们开发了新的肾/胰岛异种移植免疫抑制方案，包括这些试剂。少

Due largely to improvements in immunosuppressive therapies, organ transplantation has become the primary cure for end-stage organ failure in the United States, Europe, as well as Japan. However, the current shortage of donor organs is a critical problem. One attractive solution is xenotransplantation utilizing miniature swine donor organs. However, because human blood contains native antibodies (NAb) directed toward a constitutively expressed pig cell surface carbohydrate called galactose-alpha-1,3-galactose (Gal), pig-to-human xenotransplantation initially resulted in hyper-acute (graft loss in <1 day) humoral rejection. With this grant support in the past four years, we have made two major achievements, neither of which had previously been accomplished in Japan. Achievement 1 (first domestic success) : Using nuclear transfer from somatic nuclei of GalT-KO miniature swine, obtained from the TBRC at Harvard Medical School, we and our colleagues, as a collaborative effort, succeeded in … More producing GalT-KO miniature swine. We then transplanted GalT-KO kidneys from those pigs into cynomologous monkeys to confirm that hyperacute rejection was avoidable. Rejection did not occur for 15 days after xenotransplantation. Achievement 2 (first domestic success) : We successfully isolated islets from miniature swine and, following xenogeneic transplantation of these islets, we observed maintenance of normal blood glucose levels up to two months in monkeys. In addition, we have explored the mechanisms of rejection in xenotransplantation. In particular, our results utilizing GalT-KO swine suggested that CD59 is involved in development of accommodation. Moreover, our studies have suggested immune-regulatory/protective effects by (1) transgene human CD47 onto porcine cells and (2) administration of soluble thrombomodulin or hepatocyte growth factor. Using the support of this grant, we have developed new immunosuppressive regimens for renal/islet xenotransplantation, including these reagents. Less