Immunological mechanisms underlying T1DM pathogenesis

T1DM 发病机制的免疫学机制

• 批准号: 6421543
• 负责人: David Harlan
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6421543
• 关键词: antigen presentation; autoantigens; autoimmune disorder; cytotoxic T lymphocyte; disease /disorder model; genetically modified animals; immunomodulators; insulin dependent diabetes mellitus; laboratory mouse; pancreatic islet function

Type 1 Diabetes Mellitus (T1DM) is an autoimmune disease resulting from the T cell mediated destruction of insulin-producing beta cells located in the pancreas. Current treatment, which includes insulin replacement by injection, frequent blood glucose monitoring, and dietary/exercise discipline, can prevent death from hormonal insufficiency, but is not curative and does not prevent long-term complications. Those complications include nerve damage and vascular deterioration (large and small blood vessels) resulting in damage to various organs, including the heart, brain, kidneys, and eyes. Life expectancy is shortened by an estimated one-third compared to similar individuals but without T1DM. This work, initiated several years ago at the Naval Medical Research Institute and further developed at the University of Ulm in Germany, has characterized a unique murine model of autoimmune diabetes using rat-insulin promoter (RIP)-CD80 transgenic mice (RIP-CD80 mice). These animals are predisposed to immune mediated beta cell destruction based on their beta cell-specific expression of the costimulatory molecule CD80. While RIP-CD80 mice rarely develop spontaneous diabetes (incidence 6.7%, compared to none of wild type mice), we have observed and have initially characterized the profound susceptibility these mice display to develop progressive islet infiltration and eventually insulin dependent diabetes mellitus (IDDM) following immunization with beta cell autoantigens (i.e. protein molecules that are expressed specifically by the pancreatic beta cells of these mice). For instance, these animals, unlike non-transgenic littermates, uniformly develop islet cell destruction and IDDM upon immunization with insulin precursors, a beta cell autoantigen strongly suspected to be involved in the pathogenesis of T1DM in humans. Hence, this laboratory's objective using the above mouse model can be summarized as follows:(1) We are preparing to identify self-antigens (Ag) that are thought to be important initial target Ag for the developing autoimmune response. For this purpose, we will simply immunize RIP-CD80 transgenic mice with the various candidate auto-antigenic molecules and then follow them for the development of Ag-specific T cell responses, insulitis, and diabetes.(2) We will study beta cell specific T cell responses in an adoptive transfer model where the primary sensitization of the autoreactive T cells will take place either in vitro, or by immunizing in vivo, as proposed in (1). These studies will focus on the mechanisms of the developing beta cell destructive immune responses, as described in 1) and 2), and will attempt to identify novel approaches to interfere with the ongoing immune responses.

1型糖尿病（T1 DM）是一种自身免疫性疾病，由T细胞介导的位于胰腺中的产生胰岛素的β细胞的破坏引起。目前的治疗包括注射胰岛素替代、频繁血糖监测和饮食/锻炼纪律，可以预防因激素不足而死亡，但不能治愈，也不能预防长期并发症。这些并发症包括神经损伤和血管恶化（大血管和小血管），导致各种器官受损，包括心脏，大脑，肾脏和眼睛。与没有T1 DM的相似个体相比，预期寿命估计缩短了三分之一。这项工作，几年前在海军医学研究所开始，并在德国的乌尔姆大学进一步发展，已经使用大鼠胰岛素启动子（RIP）-CD 80转基因小鼠（RIP-CD 80小鼠）表征了独特的自身免疫性糖尿病小鼠模型。这些动物基于其共刺激分子CD 80的β细胞特异性表达而易受免疫介导的β细胞破坏。虽然RIP-CD 80小鼠很少发生自发性糖尿病（发生率为6.7%，与野生型小鼠相比无一发生），但我们已经观察到并初步表征了这些小鼠在用β细胞自身抗原（即由胰岛细胞特异性表达的蛋白质分子）免疫后显示出发生进行性胰岛浸润并最终发生胰岛素依赖性糖尿病（IDDM）的深刻易感性。 这些小鼠的胰腺β细胞）。例如，与非转基因同窝出生的动物不同，这些动物在用胰岛素前体免疫后一致地发生胰岛细胞破坏和IDDM，胰岛素前体是一种强烈怀疑参与人类T1 DM发病机制的β细胞自身抗原。因此，本实验室使用上述小鼠模型的目的可以概括如下：（1）我们正在准备鉴定被认为是发展自身免疫应答的重要初始靶抗原的自身抗原（Ag）。为此，我们将简单地用各种候选自身抗原分子免疫RIP-CD 80转基因小鼠，然后跟踪它们的Ag特异性T细胞应答、胰岛炎和糖尿病的发展。(2)我们将在过继转移模型中研究β细胞特异性T细胞应答，其中自体反应性T细胞的初级致敏将在体外或通过体内免疫发生，如（1）中所提出的。这些研究将集中在发展中的β细胞破坏性免疫反应的机制上，如1）和2）所述， 试图找出新的方法来干扰正在进行的免疫反应。