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.

抽象的 组织特异性自身免疫的发展是一个慢性过程，其中精细编程的自身免疫 尽管组织环境最终占主导地位，但反应在靶器官中进展并达到顶峰。 通过侵入性反应，具有对抗此类致病活动功能的调节元件仍然存在 在 1 型糖尿病 (T1D) 中，产生胰岛素的 β 细胞是自身反应性 T 细胞的目标。 不太受重视的是，在第一个 T 细胞进入胰岛之前。 环境已经建立了一种抑制自身免疫攻击的内在机制。 调节是由专门负责清除的胰岛驻留巨噬细胞的特定子集介导的 凋亡的 β 细胞，这一过程称为胞吞作用 胞吞作用程序可诱导抗炎作用。 反应，当增强时，会产生强大的免疫抑制功能，从而产生深刻的保护 我们努力认为胞吞作用程序可以作为一种原始的控制机制。 无论自身免疫倾向如何，都安装在正常的胰岛环境中。 在小鼠和人类中常见，可能与其他免疫调节元件（即， 调节性 T 细胞 (Treg) 是随着适应性免疫入侵而引入的。 胰岛的胞吞作用将为发生在胰岛中的生物和自身免疫事件提供概念上的进展 此外，通过分析与巨噬细胞相关的免疫抑制成分。 胞吞作用，该项目将提供与人类 T1D 相关的转化和治疗见解。 提议，我们寻求彻底检查 efferocytic 胰岛巨噬细胞，并确定它们在调节胰岛巨噬细胞中的作用 复杂的自身免疫过程。