Adaptive immunity in virus-induced diabetes in BBDR rats

' ' ' 1型糖尿病在遗传易感个体中的表达被假设为需要一个 环境触发器“然而，对人类群体中环境触发因素的研究， and exposed暴露at random随机to microbial微生物agents代理，is difficult困难.本提案的目的是了解 大鼠病毒感染如何改变免疫系统，导致糖尿病表达在遗传易感 hosts.这项研究建立在我们对8B大鼠自身免疫模型的广泛经验基础上。 糖尿病，效应调节T细胞平衡在调节糖尿病中的作用，以及我们广泛的 通过病毒感染诱导BBDR大鼠糖尿病的经验。这项提案是基于令人兴奋的 新进展：1）独特的分子试剂，慢病毒，siRNA和shRNA技术;2）最近 发现了产生和抑制T细胞无反应性的重要新因素，以及3）非- 淋巴细胞减少大鼠模型，其响应于Toll样受体（TLR）连接和病毒感染而表达糖尿病。 感染糖尿病诱导的决定因素被认为对人类很重要。 我们将使用这些新的资源来测试我们的总体假设，即病毒感染导致 通过1）诱导短暂的淋巴细胞减少状态，2）导致 降低调节性T细胞数量或活性，和3）自身反应性T细胞的优先扩增。 因为我们的模型是基于明确定义的环境扰动，我们现在可以准确地确定 遗传易感宿主对病毒感染的免疫应答如何导致 糖尿病 具体目标1是确定遗传易感和耐药宿主对病毒的免疫应答， 感染这一基本信息将用于检验我们的假设，即病毒诱导的淋巴细胞减少症是 在遗传上易患糖尿病的宿主中发展为显性糖尿病的关键因素。具体 目的2是确定病毒感染如何调节糖尿病易感细胞中的效应和调节性T细胞， 和抗性宿主。我们将使用新的方法来验证我们的假设，即病毒感染引起糖尿病 在遗传易感宿主中，通过降低Treg活性，同时诱导 自身反应性T细胞具体目标3是确定病毒感染是否调节控制TcR的因子， 无反应性T细胞这些研究将验证我们的假设，即病毒感染调节T细胞群 它们具有在糖尿病的表达中很重要的无变应性和调节性。履行 这些目标为确定预防糖尿病的相关机制提供了希望。

' ' ' Expression of type 1 diabetes in genetically susceptible individuals is hypothesized to require an 'environmental trigger." However, study of environmental triggers in human populations, which are outbred and exposed at randomto microbiological agents, is difficult. The goal of this proposalis to understand in the rat how viral infection alters the immune system to lead to diabetes expression in genetically susceptible hosts. The proposed research builds on our extensive experience with the 8B rat model of autoimmune diabetes, the role of effector to regulatory T cell balances in regulating diabetes, and our extensive experience in the induction of diabetes in BBDR rats by viral infection. This proposal is based on exciting new developments: 1) unique molecular reagents,and lentivirus, siRNA, and shRNA technology;2) recently discovered novel factors importantfor generating and maintainingT cell anergy, and 3) availability of a non- lymphopenic rat model that expresses diabetes in response to toll-like receptor (TLR) ligation and viral infectiondeterminants of diabetesinduction thought to be important in humans. We will use these novel resourcesto test our overall hypothesisthat viralinfection leads to expression of diabetes in genetically susceptible hosts by 1) inducing a transient lymphopenic state that 2) leads to decreasing regulatory T cell number or activity, and 3) preferential expansion of autoreactive T cells. Because our models are based on well defined environmental perturbants, we can now determineexactly how the immune response to infection with virus in geneticallysusceptible hosts leads to the expressionof diabetes. Specific Aim 1 is to define the.immune response of geneticallysusceptible and resistant hosts to viral infection. This fundamental information will be used to test our hypothesis that virus induced lymphopenia is a critical factor in the development of overt diabetes in hosts genetically predisposed to diabetes. Specific Aim 2 is to determine how virus infection modulates effector and regulatory T cells in diabetes-susceptible and resistant hosts. Wewill use new methodology to test our hypothesis that virus infection induces diabetes in genetically susceptible hosts by decreasing Treg activity while simultaneously inducing the expansion of autoreactive Tcells. Specific Aim 3 is to determine if virus infection modulates factors that control Tregs and anergic T cells. These studies will test our hypothesis that virus infection modulates a population of T cells that have both anergic and regulatory properties that are important in the expression of diabetes. Fulfilling these aims holds out the promise of identifying mechanisms relevantto the prevention of diabetes.