Type 1 Diabetes in Acute Pancreatitis Consortium, Pacific Northwest Clinical Center: Immune Pathogenesis of Post-Pancreatitis T1D

项目摘要/摘要 这项应用结合了弗吉尼亚州的临床优势和大量的急性胰腺炎患者。 梅森医学中心消化疾病研究所和贝纳罗亚研究所在 自身免疫与1型糖尿病的发病、临床病程和潜在机制 自身免疫介导的急性胰腺炎后糖尿病。此应用程序的基本主题是 研究胰腺炎后自身免疫性糖尿病所获得的知识将为以下方面提供关键的见解 典型1型糖尿病的发病机制。 综述和荟萃分析数据表明，几乎40%的人最终会患上糖尿病或前驱 糖尿病后急性胰腺炎。然而，关于包括的人口，有不一致的定义， 终点，以及在评估急性胰腺炎和糖尿病的研究中的随访持续时间。因此，真实的 糖尿病后胰腺炎的发病率和自然病史尚不清楚。此外，虽然一般认为 是坏死性胰岛β细胞损伤或破坏的后果，急性 胰腺炎坏死和糖尿病的发病率最近受到了质疑，但机制有限 来自动物或人体研究的数据。因此，糖尿病并发急性胰腺炎的发病机制尚不清楚。 明白了。 相比之下，典型的1型糖尿病的自然病史被很好地描述；自身抗体在遗传上是可以看到的。 高危个体，其中一些人随着时间的推移会发展成β细胞死亡，导致无症状，其次是 有症状的血糖异常最终需要外源性胰岛素治疗。有证据表明， 获得性免疫系统在这一过程中包括与II型HLA型很强的遗传关联， 身体标本中细胞浸润的存在以及适应性免疫疗法改变疾病的能力 当然了。在典型的1型糖尿病中，尚不清楚的是最初触发适应性免疫的基础是什么 系统。随着时间的推移，疾病发病率的增加表明基因-环境的相互作用导致了贝塔病毒 细胞损伤，但确定具体的触发因素仍然具有挑战性。因为胰腺损伤和先天激活 都是急性胰腺炎的已知成分，在这种情况下糖尿病的发展可以允许 研究急性组织损伤如何导致自身免疫，从而作为模型系统 了解导致典型1型糖尿病的机制。在这个提案中，我们将确定事件的发生率 和描述糖尿病的自然病史和急性胰腺炎后个体的自身免疫(目标1)，测试 一种假说，即急性胰腺炎会导致一部分人的免疫状态发生变化， 使他们易于发展胰岛自身免疫(目标2)，并确定急性胰腺炎是否与 自身免疫导致的免疫表型类似于典型的1型糖尿病(目标3)。

Project Summary / Abstract This application brings together the clinical strengths and large acute pancreatitis patient population of Virginia Mason Medical Center's Digestive Disease Institute and Benaroya Research Institute's expertise in autoimmunity and type 1 diabetes to understand the incidence, clinical course, and potential mechanisms of autoimmune mediated diabetes after acute pancreatitis. The underlying theme of this application is that knowledge gained from studying autoimmune diabetes after pancreatitis will provide key insights as to mechanisms of disease in typical type 1 diabetes. Review and meta-analysis data suggest that almost 40% of individuals will eventually develop diabetes or pre- diabetes post-acute pancreatitis. There is, however, inconsistency as to populations included, definitions of endpoints, and duration of follow-up across studies evaluating acute pancreatitis and diabetes. Thus, the true incidence and natural history of diabetes post-pancreatitis is not clear. Moreover, while generally considered to be a consequence of necrosis resulting in beta cell injury or destruction, the relationship between acute pancreatitis necrosis and incidence of diabetes has recently been questioned and there is limited mechanistic data from either animal or human studies. Thus, the etiopathology of diabetes post-acute pancreatitis is not well understood. In contrast, the natural history of typical type 1 diabetes is well described; autoantibodies are seen in genetically at-risk individuals, some of whom over time develop beta cell death leading to asymptomatic, followed by symptomatic dysglycemia eventually requiring exogenous insulin therapy. Evidence for the clear role of the adaptive immune system in this process include the strong genetic association with class II HLA type, the presence of cellular infiltrates in cadaver specimens, and the ability of adaptive immune therapy to alter disease course. What is not clear in typical type 1 diabetes is what underlies the initial triggering of the adaptive immune system. The increasing incidence of disease over time suggests gene-environment interactions leading to beta cell injury, yet it remains challenging to identify specific triggers. Since pancreatic damage and innate activation are known components of acute pancreatitis, the development of diabetes in this setting can allow for investigation as to how acute tissue injury results in autoimmunity and thus serves as a model system to understand mechanisms resulting in typical type 1 diabetes. In this proposal, we will determine the incidence and describe the natural history of diabetes and autoimmunity in individuals after acute pancreatitis (Aim 1), test the hypothesis that acute pancreatitis resolves to an altered immune state in a subset of individuals that predisposes them to develop islet autoimmunity (Aim 2), and determine if acute pancreatitis associated autoimmunity results in immune phenotypes similar to that seen in typical type 1 diabetes (Aim 3).