Immune Signatures and Clinical Outcomes in Acute Pancreatitis

项目摘要/摘要 在美国，每年花费超过3美元的急性胰腺炎(AP)患者超过300,000人 十亿美元。大多数AP病例是轻微的(MAP)，住院时间为3-4天，但约有15%的AP 受试者患上严重疾病(SAP)，定义为存在持续性器官衰竭。高达三分之一的SAP 重症监护病房的患者在重症监护病房数周后因多系统器官衰竭而死亡。到目前为止，还没有什么治疗方法 药物已经成功地改善了SAP旷日持久的医院病程。美国国立卫生研究院 糖尿病、消化和肾脏疾病研讨会确定了两个关键的知识差距，这些差距是 开发药理学干预措施：1)建立高度准确的早期预测工具 确定哪些对象在住院期间会发展为SAP；2)更深入地了解SAP 机制途径和免疫发病机制，以确定新的治疗靶点。 我们提出了马赛克研究(AP的免疫特征和临床结果)，这是一项前瞻性的多学科研究。 中心，观察队列，将解决SAP中的这两个知识差距。我们最近发现 一种新的多细胞因子小组(血管生成素-2、肝细胞生长因子、白介素8、抵抗素与肿瘤 坏死因子-α受体-1)，在疾病过程的早期准确地预测SAP，准确率为 0.89，并显著优于现有的预测工具。本项目的目标1是验证多细胞因子 在美国多个临床站点的一个庞大的、种族多样化的AP人群中的一个小组。 在初步研究中，贝纳罗亚研究所(BRI)的免疫学家已经确定了独特的免疫 单核细胞增多，T滤泡辅助细胞和记忆B细胞减少等细胞变化 AP患者与健康对照组的血样比较。在目标2中，马赛克研究将扩展这项工作 通过定义与早期AP中的细胞因子信号相对应的循环免疫细胞，并识别 免疫通路在SAP发病中的作用。这将产生第一个高维表型 分析人类AP的免疫细胞类型，为其免疫机制提供新的见解。 MOSAIC研究人员拥有NIH资助的胰腺炎和免疫学方面的补充专业知识。这个 该团队由俄亥俄州立大学出版的胰腺病学家和BRI的免疫学家领导， 由一带一路专门的生物信息学核心提供支持。它还包括另外三个学术医疗中心 具有将不同种族的人群纳入预期的AP研究试验的可靠记录。 马赛克研究的成功完成将产生以下影响：1)建立 SAP的准确、早期预测工具，2)提供对早期免疫事件的开创性洞察力 SAP基于强大的人体数据，3)识别治疗性免疫靶点以进行进一步测试，以及4) 建立美国多中心研究平台，启动临床试验，测试AP的免疫疗法。

PROJECT SUMMARY/Abstract Acute pancreatitis (AP) accounts for over 300,000 admissions in the U.S. with annual costs exceeding $3 billion. Most cases of AP are mild (MAP) with a hospital stay of 3-4 days, but approximately 15% of AP subjects develop severe disease (SAP), defined by presence of persistent organ failure. Up to a third of SAP patients expire from multi-system organ failure after weeks in the intensive care unit. To date, no therapeutic agents have been successful at ameliorating the protracted hospital course of SAP. The National Institute of Diabetes and Digestive and Kidney Diseases workshops identified two critical knowledge gaps as barriers to developing pharmacologic interventions: 1) the establishment of a highly accurate, early prediction tool to identify which subjects will develop SAP during hospitalization; 2) a more in-depth knowledge of SAP mechanistic pathways and immuno-pathogenesis to identify novel therapeutic targets. We propose the MoSAIC Study (iMmune SIgnAtures and ClIniCal outcomes in AP), a prospective multi- center, observational cohort that will address both of these knowledge gaps in SAP. We recently discovered a novel multi-cytokine panel (angiopoetin-2, hepatocyte growth factor, interleukin-8, resistin, and tumor necrosis factor-α receptor-1) that accurately predicts SAP early in the disease process with an accuracy of 0.89 and significantly outperforms existing prediction tools. Aim 1 of this project is to validate the multi-cytokine panel in a large, ethnically diverse AP population across multiple U.S. clinical sites. In preliminary studies, immunologists at the Benaroya Research Institute (BRI) have identified unique immune cell changes such as an increase in monocytes and a decrease of T follicular helper and memory B cells in blood samples of AP patients compared to healthy controls. In Aim 2, the MoSAIC study will extend this work by defining the circulating immune cells that correspond with cytokine signatures in early AP and identifying the immune pathways driving the development of SAP. This will generate the first high-dimensional phenotypic analysis of immune cell types in human AP and provide new insights into its immune mechanisms. MoSAIC investigators have NIH-funded complementary expertise in pancreatitis and immunology. The team is led by well-published pancreatologists at the Ohio State University and immunologists at BRI, supported by a dedicated bioinformatics core at BRI. It also includes three additional academic medical centers with proven track-records of enrolling ethnically diverse populations into prospective AP research trials. Successful completion of the MoSAIC study will have the following impact by: 1) establishing an accurate, early prediction tool for SAP, 2) providing groundbreaking insight into the early immune events of SAP based on robust human data, 3) identifying therapeutic immune targets for further testing, and 4) establishing a U.S. multicenter research platform for launching clinical trials to test immunotherapies in AP.