IMPACT OF PLASMACYTOID DENDRITIC CELLS ON TYPE I DIABETES PATHOGENESIS

描述(申请人提供)：慢性自身免疫性疾病影响全球数百万人，因此，具有巨大的社会、经济和政治影响。I型糖尿病(T1D)是儿童和青少年中最常见的慢性病之一；每年有超过13,000名年轻人被诊断为T1D。T细胞被认为是在T1D发育过程中破坏胰岛素产生细胞的主要参与者；然而，导致T细胞募集和胰岛炎症和破坏的启动因素在很大程度上是未知的。先天免疫缺陷涉及病毒感受器的激活和随后的I型干扰素(IFN-I)反应，已被认为与T1D的发病机制有关。在糖尿病小鼠模型中，浆细胞样树突状细胞(PDC)被认为是产生干扰素-I的主要来源，在诊断为T1D的人类患者中，已观察到产生干扰素-I的PDC的扩张。PDC是一种抗原提呈细胞，专门分泌针对病毒和内源性DNA/RNA的干扰素-I。因此，消除PDC或阻止其产生干扰素-I可能会阻止T1D的免疫病理。另一方面，在病毒诱导的T1D模型中，PDC和干扰素-I可能会减少病毒负荷并触发保护性的耐受机制。基于这些观察和我们的初步结果，本研究的长期目标是了解PDC、干扰素-I和T1D发育之间的联系。事实上，PDC是否确实促进或保护T1D，可以通过在糖尿病小鼠模型中专门消耗这些细胞来确定。我们方法背后的基本原理是，了解参与调节有害或有益免疫反应的细胞类型的性质和功能可以导致更好的治疗和治疗T1D等慢性自身免疫性疾病的策略，这可能会减轻经济负担和提高生活质量。我们提出了两个特定的目的：1.确定PDC在自身免疫性糖尿病中的作用2.为了确定PDC在病毒诱导的糖尿病中的作用，这些目的将为深入了解PDC在自身免疫和病毒诱导的T1D中的作用提供依据。我们相信，使用我们诱导PDC耗尽的尖端方法和PDC生物学专业知识来解决这些特定目标，将产生关于PDC耗竭抗体或PDC激活药物用于T1D治疗干预的潜力的宝贵信息。

DESCRIPTION (provided by applicant): Chronic autoimmune diseases affect millions of people worldwide and thus, have a tremendous social, economic and political impact. Type I diabetes (T1D) is one of the most common chronic diseases in children and adolescents; more than 13,000 young adults are diagnosed with T1D each year. T cells are considered a main player in the destruction of insulin-producing -cells during T1D development; however, the initiating factors contributing to T cell recruitment and islet inflammation and destruction are largely unknown. Innate immune defects involving activation of viral sensors and subsequent type I interferon (IFN-I) responses have been implicated in the pathogenesis of T1D. Plasmacytoid dendritic cells (pDC) have been identified as a major source of IFN-I in diabetic mouse models and an expansion of IFN-I-producing pDC has been observed in human patients with T1D around the time of diagnosis. pDC are antigen presenting cells that specialize in the secretion of IFN-I in response to both viral and endogenous DNA/RNA. Thus, elimination of pDC or blocking their IFN-I production may prevent immunopathology in T1D. On the other hand, in models of virus-induced T1D, pDC and IFN-I may reduce viral burden and trigger tolerogenic mechanisms that are protective. Based on these observations and our preliminary results, the long-term goal of this study is to understand the link between pDC, IFN-I and T1D development. Whether pDC do, in fact, promote or protect against T1D, can be firmly established by specifically depleting these cells in diabetic mouse models. The rationale behind our approach is that understanding the nature and function of the cell types involved in mediating detrimental or beneficial immune responses can lead to better treatment and therapeutic strategies for chronic autoimmune diseases such as T1D, that might ease financial burden and improve quality of life. We propose two specific aims: Specific Aim 1. To determine the impact of pDC on autoimmune diabetes Specific Aim 2. To determine the impact of pDC on virus-induced diabetes These aims will provide insights into roles of pDC during autoimmune and virus-induced T1D. We are confident that addressing these specific aims using our cutting edge approach for inducing pDC depletion and expertise in pDC biology will yield invaluable information regarding the potential of pDC- depleting antibodies or pDC-activating drugs for therapeutic intervention in T1D.