Autoimmune Diabetes: Macrophage Responses

自身免疫性糖尿病：巨噬细胞反应

• 批准号: 10570970
• 负责人: Xiaoxiao Wan
• 金额: $ 46.8万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-14 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570970
• 关键词: Anti-Inflammatory Agents; Antigen Presentation Pathway; Antiinflammatory Effect; Apoptotic; Autoimmune; Autoimmune Diabetes; Autoimmune Process; Autoimmune Responses; Autoimmunity; Beta Cell; Biological; Biology; Bystander Suppression; Cell Communication; Chronic; Complex; Development; Disease; Elements; Environment; Event; Human; Immune; Immunosuppression; Inflammatory Response; Insulin; Insulin-Dependent Diabetes Mellitus; Invaded; Islets of Langerhans; Macrophage; Mediating; Modeling; Molecular; Mus; Organ; Pathogenicity; Process; Receptor Protein-Tyrosine Kinases; Regulation; Regulatory Element; Regulatory T-Lymphocyte; Role; Streptozocin; T cell infiltration; T-Lymphocyte; Therapeutic; Tissues; autoimmune pathogenesis; autoreactive T cell; diabetogenic; immunoregulation; insight; islet; prevent; programs; response; restraint

ABSTRACT The development of tissue-specific autoimmunity is a chronic process in which finely programmed autoimmune responses progress and culminate in the target organ. Although the tissue environment is eventually dominated by the invasive responses, regulatory elements that function to oppose such pathogenic activities remain understudied. In type 1 diabetes (T1D), the insulin-producing β cells are targeted by self-reactive T cells infiltrating into the pancreatic islets. Less appreciated is that before the entry of the first T cells, the islet environment has established an intrinsic mechanism that restrains the onward autoimmune attack. Such regulation is mediated by a specific subset of the islet resident macrophages specialized in the clearance of apoptotic β cells, a process referred to as efferocytosis. The efferocytosis program induces anti-inflammatory responses and when enhanced, imposes strong immunoinhibitory functions, leading to profound protection from autoimmune diabetes. We hypothesize that the efferocytosis program may act as an original control mechanism installed in the normal islet environment regardless of autoimmune propensity. This innate mechanism is common in mice and humans and may considerably differ from other immunomodulatory elements (i.e., regulatory T cells (Tregs)), which are introduced along with the adaptive immune invasion. Therefore, examining efferocytosis in islets will provide conceptual advances to the biological and autoimmune events taking place in this important organ. Moreover, by analyzing the immunoinhibitory components associated with macrophage efferocytosis, this project will provide translational and therapeutical insights relevant to human T1D. In this proposal, we seek to thoroughly examine the efferocytic islet macrophages and define their role in regulating a complex autoimmune process.

摘要 组织特异性自身免疫的发展是一个慢性过程，其中精细程序化的自身免疫性免疫性疾病是一种免疫性疾病。 反应进行并在靶器官中达到顶点。尽管组织环境最终被 通过侵入性反应，抵抗这种致病活动的调节元件仍然存在， 替补演员在1型糖尿病（T1D）中，产生胰岛素的β细胞被自身反应性T细胞靶向 渗透到胰岛中不太了解的是，在第一个T细胞进入之前，胰岛 环境已经建立了一种内在的机制，抑制了向前的自身免疫攻击。等 调节是由胰岛驻留巨噬细胞的特定亚群介导的，所述巨噬细胞专门清除 凋亡β细胞，这一过程被称为巨噬细胞增多。红细胞增多症程序诱导抗炎 当增强时，会产生强烈的免疫抑制功能，从而产生深刻的保护作用， 自身免疫性糖尿病我们推测，红细胞增多症程序可能作为一个原始的控制机制， 安装在正常的胰岛环境中，而不管自身免疫倾向如何。这种先天机制是 在小鼠和人中是常见的并且可能与其它免疫调节元件有相当大的不同（即， 调节性T细胞（T细胞）），其与适应性免疫侵袭一起沿着引入。因此，检查 胰岛中的红细胞增多症将为胰岛中发生的生物学和自身免疫事件提供概念上的进展。 这个重要的器官。此外，通过分析与巨噬细胞相关的免疫抑制成分， 该项目将提供与人类T1D相关的翻译和治疗见解。在这 我们试图彻底检查巨噬细胞胰岛巨噬细胞，并确定它们在调节细胞凋亡中的作用。 复杂的自身免疫过程