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，会破坏胰腺产生胰岛素的细胞。这种疾病影响了大约一百万美国人，通常在儿童期或成年早期发病。它严重损害了生活质量，从而给受影响的家庭带来了沉重的经济负担。移植产生胰岛素的人类同种异体胰岛已成为该疾病的治疗方法。然而，目前的免疫抑制治疗的许多并发症对于患有 1 型糖尿病的年轻患者来说尤其严重。然而，他们尤其受益于胰岛移植。因此，对于这些年轻患者来说，开发新的免疫抑制方案尤为重要，该方案可诱导对移植物的长期无反应（如果不是耐受性），并且是短期且无毒的。 我们将在本申请中讨论如何调整否决免疫抑制以诱导对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。我们生产了腺病毒载体，可以有效地将 CD8 a 链的表达转移到不同的组织。这些载体在体外和体内均诱导有效且特异性的抑制性 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完全同种异体胰岛移植物免受排斥。移植物的短期离体调节足以防止它们的排斥反应，从而允许它们在正常的、非免疫受损的小鼠中长期存活。我们现在建议建立此类否决载体的临床相关性，以测试其在胰岛移植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，即非肥胖糖尿病（NOD）小鼠。