Protecting Pancreatic Islet Grafts from Rejection

保护胰岛移植物免遭排斥

• 批准号: 6859237
• 负责人: Uwe D. Staerz
• 金额: $ 43.34万
• 依托单位: ISOGENIS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6859237
• 关键词: Adenoviridae; NOD mouse; adeno associated virus group; artificial immunosuppression; biotechnology; cytoprotection; diabetes mellitus therapy; immune response; immune tolerance /unresponsiveness; immunocytochemistry; immunofluorescence technique; immunotherapy; insulin dependent diabetes mellitus; laboratory mouse; leukocyte activation /transformation; microarray technology; pancreatic islet transplantation; transfection /expression vector; transplant rejection

DESCRIPTION (provided by applicant): Type I diabetes mellitus is an autoimmune disease that destroys the insulin-producing cells of the pancreas. This disease affects an estimated one million Americans and usually finds its onset in childhood or in young adulthood. It significantly impairs the quality of live and thus puts a significant economic burden on the families of the afflicted. The transplantation of insulin-producing human allogeneic pancreatic islets has been as a curative treatment of the disease. However, the many complications of present immune suppressive therapy are especially grave for the young patients afflicted with type 1 diabetes. Yet, they would especially benefit from pancreatic islet transplantation. Therefore, it is especially important for these young patients to develop novel immune suppression protocols that induce long-term unresponsiveness, if not tolerance, towards the graft and that are short-term and non-toxic. We will discuss in this application how veto immune inhibition can be adapted to induce long-term acceptance of allogeneic grafts. Our arguments are based on the following experimental observations. We had produced Adenoviral vectors that efficiently transferred the expression of the CD8 a-chain to different tissues. These vectors induced efficient, yet specific inhibition T lymphocytes both in vitro and in vivo. In additional experiments, we could demonstrate that these Adenoviral vectors permanently protected fully allogeneic pancreatic islet grafts from rejection. A short-term ex vivo conditioning of the transplant was sufficient to prevent their rejection and thus to permit their long-term survival in normal, non-immune compromised mice. We now propose to produce clinical correlates of such veto vectors, to test their efficacy and toxicity in mouse models of pancreatic islet transplantation and to expand these transplantation studies into mice suffering from autoimmune diabetes, i.e. into non-obese diabetic (NOD) mice.

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