IMPACT OF PLASMACYTOID DENDRITIC CELLS ON TYPE I DIABETES PATHOGENESIS

描述（由申请人提供）：慢性自身免疫性疾病影响全世界数百万人，因此具有巨大的社会、经济和政治影响。1型糖尿病（T1D）是儿童和青少年最常见的慢性疾病之一；每年有超过13000名年轻人被诊断为T1D。在T1D的发展过程中，T细胞被认为是破坏胰岛素产生细胞的主要参与者；然而，促进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。涉及病毒传感器激活和随后的I型干扰素（IFN-I）应答的先天免疫缺陷与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）已被确定为IFN-I的主要来源，并且在T1D患者诊断前后观察到产生IFN-I的pDC的扩增。pDC是抗原呈递细胞，专门分泌ifn - 1以应对病毒和内源性DNA/RNA。因此，消除pDC或阻断其IFN-I的产生可能会阻止T1D的免疫病理。另一方面，在病毒诱导的T1D模型中，pDC和IFN-I可能会减少病毒负担并触发具有保护性的耐受性机制。基于这些观察结果和我们的初步结果，本研究的长期目标是了解pDC、IFN-I与T1D发展之间的联系。通过在糖尿病小鼠模型中特异性消耗这些细胞，可以确定pDC是否真的促进或保护T1D。我们的方法背后的基本原理是，了解参与介导有害或有益免疫反应的细胞类型的性质和功能，可以为慢性自身免疫性疾病（如T1D）提供更好的治疗和治疗策略，从而减轻经济负担并提高生活质量。我们提出两个具体目标：确定pDC对自身免疫性糖尿病特异性靶2的影响。为了确定pDC对病毒诱导的糖尿病的影响，这些目标将为pDC在自身免疫和病毒诱导的T1D中的作用提供见解。我们相信，利用我们诱导pDC耗竭的尖端方法和pDC生物学的专业知识来解决这些具体目标，将产生关于pDC耗竭抗体或pDC激活药物在T1D治疗干预方面的潜力的宝贵信息。

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.