| Project/Area Number |
19209043
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General surgery
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| Research Institution | Kagoshima University |
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Principal Investigator |
YAMADA Kazuhiko Kagoshima University, フロンティアサイエンス研究推進センター, 教授 (40241103)
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| Co-Investigator(Kenkyū-buntansha) |
ODAN Hideki 広島大学, 大学院・医歯学総合研究科, 教授 (10363061)
OKITSU Teru 京都大学, 医学(系)研究科(研究院), 助教 (10378672)
NAGASHIMA Hiroshi 明治大学, 農学部, 教授 (50318664)
SAITO Toshiki 日本生物科学研究所, 付属実験動物研究所, 主任研究員 (00162214)
SATO Masahiro 鹿児島大学, フロンティアサイエンス研究推進センター, 教授 (30287099)
KAMIMURA Ryozo 鹿児島大学, フロンティアサイエンス研究推進センター, 准教授 (30253884)
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| Co-Investigator(Renkei-kenkyūsha) |
SHIMIZU Akira 日本医科大学, 医学部, 准教授 (00256942)
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| Project Period (FY) |
2007 – 2010
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| Project Status |
Completed (Fiscal Year 2010)
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| Budget Amount *help |
¥49,400,000 (Direct Cost: ¥38,000,000、Indirect Cost: ¥11,400,000)
Fiscal Year 2010: ¥12,090,000 (Direct Cost: ¥9,300,000、Indirect Cost: ¥2,790,000)
Fiscal Year 2009: ¥12,090,000 (Direct Cost: ¥9,300,000、Indirect Cost: ¥2,790,000)
Fiscal Year 2008: ¥12,090,000 (Direct Cost: ¥9,300,000、Indirect Cost: ¥2,790,000)
Fiscal Year 2007: ¥13,130,000 (Direct Cost: ¥10,100,000、Indirect Cost: ¥3,030,000)
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| Keywords | 異種移植 / ブタ・サル間移植 / 腎移植 / 膵島移植 / GalKOブタ / 遺伝子導入 / hCD47 / 免疫寛容 |
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| Research Abstract |
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
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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
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