Mechanisms by which IL-10 limits Toll-like Receptor 9 mediated Macrophage Activat

IL-10 限制 Toll 样受体 9 介导的巨噬细胞激活的机制

• 批准号: 8398178
• 负责人: Scott William Canna
• 金额: $ 5.94万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8398178
• 关键词: Acute; Adoptive Transfer; Age; Animal Model; Antigen Presentation; B-Lymphocytes; Blood Coagulation Disorders; Bone Marrow Transplantation; CD8B1 gene; Cell-Mediated Cytolysis; Cells; Characteristics; Childhood; Chronic Childhood Arthritis; Clinical; Clinical Trials; Coagulation Process; Complex; Complication; Data; Development; Diagnosis; Disease; Emergency Situation; Fever; Functional disorder; Gene Mutation; Genetic; Goals; Hemophagocytic Lymphohistiocytoses; Hepatic; Hepatitis; Histiocytosis haematophagic; Histologic; Human; Immune; Immune system; Immunologics; Immunosuppression; Infection; Inflammation; Inflammatory; Interferon Type II; Interferons; Interleukin-10; Lead; Life; Lymphocyte; Macrophage Activation; Malignant - descriptor; Mediating; Modeling; Mus; Mutation; Organ; Patients; Phenotype; Production; Rag1 Mouse; Regulation; Research; Rheumatism; Rheumatology; Role; Sepsis; Serological; Serum; Signal Transduction; Source; Syndrome; T-Lymphocyte; TLR9 gene; Toll-like receptors; Wild Type Mouse; Work; body system; cytokine; familial hemophagocytic lymphohistiocytosis; interleukin-10 receptor; killings; macrophage; mouse model; prevent

DESCRIPTION (provided by applicant): Macrophage Activation Syndrome (MAS) is an uncommon but potentially life-threatening complication of many infectious, malignant and rheumatic diseases. It is characterized by fever, difficulty clotting and multiple organ dysfunctio in the setting of overwhelming inflammation. MAS shares features with other cytokine storm syndromes including sepsis and Hemophagocytic Lymphohistiocytosis (HLH). Patients with a primary form of HLH have genetic defects in the machinery necessary for killing by immune cells, and usually die at a young age unless they receive potent immunosuppression and bone marrow transplant. Patients with MAS, however, have no such genetic defects, and very little is known about the genetic, environmental, and/or immunologic causes of MAS. Current animal models of HLH/MAS are confounded by the use of genetic mutations and/or infection. Previous work has shown that repeated stimulation through Toll-like Receptor 9 (TLR9) leads to a syndrome very similar to MAS in wild-type mice. TLR9-driven MAS requires interferon gamma (IFN¿), and hepatitis in this model is worse in mice deficient in B and T lymphocytes. Mice repeatedly stimulated through TLR9 who are unable to signal through the interleukin 10 (IL-10) receptor develop much more severe disease, underscoring the critical role of IL-10 as a negative regulator of MAS. The overall purpose of the proposed research is to define the mechanisms by which IL-10 limits the development of severe MAS. Specifically, this study aims to expand on the finding that hepatic T cells may be important sources of IL-10, and thereby are regulators of MAS. We aim to determine whether these cells are necessary and/or sufficient for preventing severe disease. A better understanding of the regulation of TLR9-driven disease will be beneficial to knowing more about how patients develop MAS, and how best to diagnose and treat this potentially fatal condition. PUBLIC HEALTH RELEVANCE: Macrophage Activation Syndrome (MAS) is a potentially fatal complication of many inflammatory diseases that is characterized by fever, clotting problems, and multiple organ dysfunction. The current understanding of MAS is poor and thus its diagnosis and treatment are difficult and highly variable. The proposed study hopes to determine how the immune system protects itself against MAS by expanding on a newly-developed mouse model, with the goal of gaining a better understanding of how best to diagnose and treat this life-threatening disease.

描述（由申请人提供）：巨噬细胞活化综合征（MAS）是一种罕见的，但可能危及生命的并发症，许多感染性，恶性和风湿性疾病。它的特征是发热，凝血困难和多器官功能障碍，在严重炎症的情况下。MAS与其他细胞因子风暴综合征（包括败血症和噬血细胞性巨噬组织细胞增多症（HLH））具有共同特征。患有原发性HLH的患者在免疫细胞杀伤所需的机制中存在遗传缺陷，并且通常在年轻时死亡，除非他们接受有效的免疫抑制和骨髓移植。然而，MAS患者没有这种遗传缺陷，并且对MAS的遗传、环境和/或免疫原因知之甚少。目前的HLH/MAS动物模型受到基因突变和/或感染的混淆。先前的工作表明，通过Toll样受体9（TLR 9）的重复刺激导致与野生型小鼠中的MAS非常相似的综合征。TLR 9驱动的MAS需要干扰素γ（IFN），而在该模型中，缺乏B和T淋巴细胞的小鼠的肝炎更严重。通过TLR 9反复刺激的小鼠无法通过白细胞介素10（IL-10）受体发出信号，从而发展出更严重的疾病，这强调了IL-10作为MAS负调节因子的关键作用。拟议研究的总体目的是确定IL-10限制严重MAS发展的机制。具体而言，本研究旨在扩大肝T细胞可能是IL-10的重要来源，从而是MAS的调节剂的发现。我们的目标是确定这些细胞是否是预防严重疾病所必需的和/或足够的。更好地了解TLR 9驱动的疾病的调节将有助于更多地了解患者如何发展MAS，以及如何最好地诊断和治疗这种潜在的致命疾病。 公共卫生关系：巨噬细胞活化综合征（MAS）是许多炎症性疾病的潜在致命并发症，其特征在于发热、凝血问题和多器官功能障碍。目前对MAS的认识很差，因此其诊断和治疗很困难且变化很大。这项拟议的研究希望通过扩展新开发的小鼠模型来确定免疫系统如何保护自己免受MAS的侵害，目的是更好地了解如何最好地诊断和治疗这种危及生命的疾病。