Transgenic studies on the control of immune responses against transplanted islets.

• Project/Area Number: 10671034
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Endocrinology
• Research Institution: Osaka University
• Principal Investigator: TASHIRO Fumi Osaka University Medical School, Assistant Professor, 医学系研究科, 助手 (40136213)
• Project Period (FY): 1998 – 1999
• Project Status: Completed (Fiscal Year 1999)
• Budget Amount: ¥2,600,000 (Direct Cost: ¥2,600,000); Fiscal Year 1999: ¥900,000 (Direct Cost: ¥900,000); Fiscal Year 1998: ¥1,700,000 (Direct Cost: ¥1,700,000)
• Keywords: transplantation / NOD mice / transgenic

Research Abstract

The number of the diabetes is over 5 million in Japan, and this number is further increasing. New therapeutic approaches are needed which can replace the conventional therapies using insulin and anti-diabetes drugs. The cytotoxicity of reactive oxygen intermediates (ROIs) has been implicated in the destruction of pancreatic β cells in insulin-dependent diabetes mellitus (IDDM). Thioredoxin (TRX), a redox (reduction/oxidation) -active protein, has recently been shown to protect cells from oxidative stress and apoptosis. To elucidate the roles of oxidative stress in the development of autoimmune diabetes in vivo, we produced nonobese diabetic transgenic mice that overexpress TRX in their pancreatic β cells. In these transgenic mice, the incidence of diabetes was markedly reduced, whereas the development of insulitis was not prevented. Moreover, induction of diabetes by streptozotocin, an ROI-generating agent, was also attenuated by TRX overexpression in β cells. This is the first direct demonstration that an antioxidative and antiapoptotic protein β cells in vivo against both autoimmune and drug-induced diabetes. Our results strongly suggest that oxidative stress plays an essential role in the destruction of β cells by infiltrating inflammatory cells in IDDM.

Research Products

• [Publications] Nitta, Y. et al: "Systemic delivery of IL-10 by intramuscular injection of expression plasmid DNA prevents autoimmune diabetes in nonobese diabetic mice"Human Gene Ther.. 9. 1701-1707 (1998)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Hotta, M. et al: "Pancreatic β-cell-specific expression of thioredoxin, an antioxidative and antiapoptotic protein, prevents autoimmune and streptozotocin-induced siabetes"J. Exp. Med.. 188. 1445-1451 (1998)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Nitta, Y. et al.: "Systemic delivery of IL-10 by intramuscular injection of expression plasmid DNA prevents autoimmune diabetes in nonobese diabetic mice."Human Gene Ther. 9. 1701-1707 (1998)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Hotta, M. et al.: "Pancreatic β-cell-specific expression of thioredoxin, an antioxidative and antiapoptotic protein, prevents autoimmune and streptozotocin-induced diabetes."J. Exp. Med. 188. 1445-1451 (1998)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Nitta Y.et al.: "Systemic delivery of IL-10 by intramuscular injection of expression plasmid DNA prevents autoimmune diabetes in nonobese diabetic mice"Human Gene Ther.. 9. 1701-1707 (1998)
• [Publications] Hotta M.et al.: "Pancreatic β-cell-specific expression of thioredoxin, an antioxidative and antiapoptotic protein, prevents autoimmune and streptozotocin-induced diabetes"J.Exp.Med.. 188. 1445-1451 (1998)