GalT-knockout pig to monkey xenogeneic kidney and islet transplantation

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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