Immunological mechanisms underlying T1DM pathogenesis

1型糖尿病（T1DM）是一种自身免疫性疾病，由T细胞介导的胰腺中产生胰岛素的β细胞的破坏引起。目前的治疗包括注射胰岛素替代、频繁的血糖监测和饮食/运动纪律，可以防止激素不足导致的死亡，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。与没有糖尿病的同类相比，预期寿命缩短了约三分之一。这项工作几年前在海军医学研究所开始，并在德国乌尔姆大学进一步发展，利用大鼠胰岛素启动子(RIP)-CD80转基因小鼠（RIP-CD80小鼠）表征了一种独特的自身免疫性糖尿病小鼠模型。基于它们的共刺激分子CD80的β细胞特异性表达，这些动物倾向于免疫介导的β细胞破坏。虽然RIP-CD80小鼠很少发生自发性糖尿病（发病率6.7%，与野生型小鼠相比没有），但我们已经观察到并初步表征了这些小鼠在免疫β细胞自身抗原（即由β细胞特异性表达的蛋白质分子）后表现出的发展进行性胰岛浸润和最终胰岛素依赖型糖尿病（IDDM）的深刻易感性

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.