IMPACT OF PLASMACYTOID DENDRITIC CELLS ON TYPE I DIABETES PATHOGENESIS

浆细胞样树突状细胞对 I 型糖尿病发病机制的影响

• 批准号: 8508393
• 负责人: MELISSA SWIECKI
• 金额: $ 14.2万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8508393
• 关键词: Address; Adolescent; Affect; Age; Antibodies; Antigen-Presenting Cells; Antigens; Apoptotic; Autoimmune Diabetes; Autoimmune Process; Autoimmunity; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Survival; Cells; Cellular biology; Child; Chronic Disease; Coupled; Cytotoxic T-Lymphocytes; DNA; Defect; Dendritic Cells; Development; Diabetes Mellitus; Diabetic mouse; Diagnosis; Disease; Economics; Gene Targeting; Goals; Human; Immune; Immune response; Inbred NOD Mice; Incidence; Infiltration; Inflammation; Insulin; Insulin-Dependent Diabetes Mellitus; Interferon Type I; Interferons; Lead; Link; Mediating; Memory; Modeling; Mus; Nature; Outcome; Pancreas; Pathogenesis; Patients; Pharmaceutical Preparations; Production; Quality of life; RNA; Rattus; Role; Signal Transduction; Source; T cell response; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Time; Transgenic Mice; United States; Viral; Viral Load result; Viral Proteins; Virus; Virus Diseases; Work; base; cell type; chemokine; chronic autoimmune disease; diphtheria toxin receptor; immunopathology; improved; insight; islet; lymph nodes; mouse model; novel; prevent; promoter; public health relevance; response; sensor; social; young adult

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.

描述（由申请人提供）：慢性自身免疫性疾病影响着全世界数百万人，因此具有巨大的社会、经济和政治影响。 I型糖尿病（T1D）是儿童和青少年最常见的慢性疾病之一；每年有超过 13,000 名年轻人被诊断患有 T1D。 T 细胞被认为是 T1D 发展过程中破坏胰岛素产生细胞的主要参与者；然而，导致 T 细胞募集以及胰岛炎症和破坏的起始因素在很大程度上尚不清楚。涉及病毒传感器激活和随后的 I 型干扰素 (IFN-I) 反应的先天免疫缺陷与 T1D 的发病机制有关。浆细胞样树突状细胞 (pDC) 已被确定为糖尿病小鼠模型中 IFN-I 的主要来源，并且在人类 T1D 患者中在诊断前后观察到产生 IFN-I 的 pDC 扩增。 pDC 是抗原呈递细胞，专门响应病毒和内源 DNA/RNA 分泌 IFN-I。因此，消除 pDC 或阻断其 IFN-I 产生可能会预防 T1D 的免疫病理学。另一方面，在病毒诱导的 T1D 模型中，pDC 和 IFN-I 可能会减少病毒负荷并触发保护性耐受机制。根据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 和 T1D 发育之间的联系。事实上，pDC 是否确实促进或预防 T1D，可以通过在糖尿病小鼠模型中特异性去除这些细胞来确定。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 T1D 等慢性自身免疫性疾病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。我们提出了两个具体目标： 具体目标 1. 确定 pDC 对自身免疫性糖尿病的影响 具体目标 2. 确定 pDC 对病毒诱导的糖尿病的影响 这些目标将深入了解 pDC 在自身免疫和病毒诱导的 T1D 中的作用。我们相信，利用我们诱导 pDC 耗竭的尖端方法和 pDC 生物学专业知识来解决这些具体目标，将产生有关 pDC 耗竭抗体或 pDC 激活药物用于 T1D 治疗干预潜力的宝贵信息。