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.

描述（由申请人提供）： I型糖尿病是一种自身免疫性疾病，可破坏胰腺的产生胰岛素细胞。这种疾病会影响大约100万美国人，通常会在童年或成年时发现其发作。它极大地损害了生活质量，因此给受苦的家属带来了重大的经济负担。产生胰岛素的人类同种异体胰岛的移植已成为对疾病的治疗方法。但是，目前免疫抑制疗法的许多并发症对于患有1型糖尿病的年轻患者特别严重。但是，它们尤其会受益于胰岛移植。因此，对于这些年轻患者而言，制定新型免疫抑制方案尤其重要，这些方案会引起长期无响应（即使不是耐受）的嫁接，并且短期且无毒。 我们将在此应用中讨论如何将否决权抑制作用适应以诱导同种异体移植物的长期接受。我们的论点基于以下实验观察结果。我们产生的腺病毒载体有效地将CD8 A链的表达转移到了不同​​的组织中。这些载体在体外和体内诱导了有效的，但特异性抑制作用T淋巴细胞。在其他实验中，我们可以证明这些腺病毒载体永久保护了完全同种同种异体胰岛移植物免受排斥反应。移植的短期离体调节足以防止其排斥反应，从而允许其在正常的非免疫损害小鼠中长期生存。现在，我们提议产生这种否决载体的临床相关性，以测试其在胰岛移植的小鼠模型中的功效和毒性，并将这些移植研究扩展到患有自身免疫性糖尿病的小鼠中，即，即非肥胖糖尿病（NOD）小鼠。