Protecting Pancreatic Islet Grafts from Rejection

描述(由申请人提供)： I型糖尿病是一种自身免疫性疾病，会破坏胰腺的胰岛素分泌细胞。据估计，这种疾病影响着100万美国人，通常在儿童或成年后发病。它严重损害了生活质量，从而给受灾者的家庭带来了巨大的经济负担。移植产生胰岛素的人类同种异体胰岛一直是治疗这种疾病的一种有效方法。然而，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来说尤其严重。然而，他们将特别受益于胰岛移植。因此，对于这些年轻患者来说，开发新的免疫抑制方案尤其重要，这些方案可以诱导对移植物的长期无反应，如果不是耐受性的，并且是短期的和无毒的。 在这项申请中，我们将讨论如何调整否决权免疫抑制，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。我们已经研制出能够有效地将CD8 a链的表达转移到不同组织的腺病毒载体。这些载体在体外和体内都能诱导高效而特异的抑制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地保护完全同种异体胰岛移植物免受排斥反应。移植的短期体外调节足以防止它们的排斥反应，从而允许它们在正常的、非免疫功能受损的小鼠中长期存活。我们现在建议建立这些否决载体的临床相关性，在小鼠胰岛移植模型中测试它们的有效性和毒性，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。

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.