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 环境诱因。然而，对人类种群中的环境诱因的研究，这些环境诱因是异种繁殖的 并随机暴露于微生物制剂，是很困难的。本提议的目标是在 病毒感染如何改变免疫系统导致糖尿病在遗传易感人群中的表达 主持人。这项拟议的研究建立在我们对8B大鼠自身免疫模型的丰富经验基础上 糖尿病，调节T细胞平衡的效应者在调节糖尿病中的作用，以及我们广泛的 用病毒感染诱导Bbdr大鼠糖尿病的经验。这项提议是基于激动人心的 新进展：1)独特的分子试剂，以及慢病毒、siRNA和shRNA技术；2)最近 发现了产生和维持T细胞无能的重要新因素，以及3)非 Toll样受体(TLR)结扎和病毒诱导的淋巴细胞减少症大鼠模型 糖尿病的感染决定因素被认为是人类的重要诱因。 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 遗传易感宿主中的糖尿病，通过1)诱导短暂的淋巴细胞减少状态，2)导致 调节性T细胞数量或活性下降，以及3)自身反应性T细胞优先扩增。 由于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反应如何导致其表达 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反应 感染。这一基本信息将被用来检验我们的假设，即病毒引起的淋巴细胞减少症 在遗传上易患糖尿病的宿主中发生显性糖尿病的关键因素。特定的 目的2是确定病毒感染如何调节糖尿病易感性患者的效应和调节性T细胞 和抵抗力强的宿主。我们将使用新的方法来验证我们的假设，即病毒感染会导致糖尿病 在遗传敏感宿主中通过降低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Tregs和Tregs的因素 无能T细胞。这些研究将检验我们的假设，即病毒感染调节T细胞数量 它们同时具有无能和调节特性，这些特性在糖尿病的表达中很重要。满足感 这些目标为确定与预防糖尿病相关的机制提供了希望。

' ' ' 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.