How do Viral Infections induce and/or enhance autoimmunity

病毒感染如何诱导和/或增强自身免疫

• 批准号: 6746544
• 负责人: Matthias G. Von Herrath
• 金额: $ 24.22万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6746544
• 关键词: Coxsackievirus; NOD mouse; antigen presenting cell; autoimmune disorder; autoimmunity; cytotoxic T lymphocyte; enzyme linked immunosorbent assay; flow cytometry; histology; immune response; insulin dependent diabetes mellitus; lymphocytic choriomeningitis virus; pancreatic islets; polymerase chain reaction; virus infection mechanism

The goal of this project is to better understand mechanistically, how viral infections could be involved in the pathogenesis of type 1 diabetes (T1 D) using the NOD and RIP-LCMV mouse models. Our approach is based on the hypothesis (which also unifies this PPG) that viruses, even if they are incapable of causing autoimmune disease per se, will modulate an ongoing autoimmune process or, conversely, provide 'fertile field' for autoaggressive lymphocytes. Our preliminary data indicate that Coxsackie Virus B3 (CVB) as well as LCMV cross-reactive viruses can accelerate the diabetogenic process and result in clinical disease, when the infection occurs during a susceptible period in prediabetic mice. Based on these findings we wish to deepen our mechanistic insight and will address the following 3 aims: 1. How does CVB accelerate T1 D? Evaluation of bystander effects (cytokines, in analogy to Dr. Fujinami's approach) that affect the aggressive response and antigen presenting cells (immunoproteasome activation in collaboration with Dr. Whitton). 2. Do subdominant viral responses accelerate disease if they encounter a 'fertile field' in the pancreas/islets, and which qualities needs the viral infection provide to achieve this? 3. Which type of viral infections will provide a diabetogenic environment for autoreactive CD8+ clones and which factors are essential (collaboration with Dr. Whitton and Fujinami)? Mechanistic insight will help us to search for causative agents in human patients at risk to develop T1D.

该项目的目的是更好地理解机理，如何使用点头和RIP-LCMV小鼠模型如何参与1型糖尿病（T1 D）的发病机理。我们的方法是基于病毒的假设（也统一了该PPG），即使它们无法引起自身免疫性疾病本身，它们也将调节持续的自身免疫过程，或者相反，为自脂型淋巴细胞提供“肥沃场”。我们的初步数据表明，当感染发生在糖尿病性小鼠的易感性期间时，当感染发生时，Coxsackie病毒B3（CVB）以及LCMV交叉反应病毒可以加速糖尿病生成过程并导致临床疾病。根据这些发现，我们希望加深我们的机械见解，并将解决以下3个目标： 1。CVB如何加速T1 D？评估旁观者效应（与博士类似的细胞因子类似 影响侵略性反应和抗原呈递细胞的富士式方法） （与Whitton博士合作激活免疫蛋白酶体）。 2。如果在 胰腺/胰岛，哪些品质需要病毒感染为实现这一目标吗？ 3。哪种类型的病毒感染将为自动反应性CD8+提供糖尿病的环境 克隆以及哪些因素是必不可少的（与惠顿博士和藤原博士的合作）？ 机械洞察力将帮助我们寻找有发展T1D风险的人类患者的因果剂。