The role of interleukin 23 in lupus

白细胞介素23在狼疮中的作用

• 批准号: 8466286
• 负责人: Vasileios Christos Kyttaris
• 金额: $ 37.19万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-14 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8466286
• 关键词: Adverse effects; Affect; American; Animals; Antibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; B-Lymphocytes; Biological Response Modifier Therapy; Cells; Chronic; Development; Disease; Disease Progression; Disease remission; Dose; Event; Flare; Generations; Goals; Human; Immune; Immune response; Immune system; Immunologics; Immunosuppressive Agents; In Vitro; Inflammation; Inflammatory; Interleukin-17; Joints; Kidney; Lead; Lupus; Lymphocyte; Lymphoid; Maintenance; Mediating; Mediator of activation protein; Mus; Nephritis; Organ; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pilot Projects; Play; Production; Receptor Signaling; Relapse; Reporting; Rheumatoid Arthritis; Role; Signal Pathway; Signal Transduction; Skin; Source; Spleen; Staging; Symptoms; Systemic Lupus Erythematosus; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Work; base; cytokine; cytotoxic; immunoregulation; interleukin-23; lupus prone mice; lupus-like; lymph nodes; mouse model; peripheral blood; receptor; receptor-mediated signaling; response; systemic autoimmune disease

DESCRIPTION (provided by applicant): The treatment of systemic lupus erythematosus (SLE), a systemic autoimmune disease that affects many organs such as the joints, skin and kidneys, is based on non-specific immunosuppressive medications that are often ineffective and have very significant side effects. In order to develop more specific less toxic medications, we need a better understanding of the exact steps that lead and then maintain the abnormal autoimmune response in SLE. Recently, a particular T cell subset that expresses the pro-inflammatory cytokine IL-17 has been shown to be present in the kidneys and peripheral blood of patients with SLE. IL-17 producing cells can induce both local inflammation in the target-organs and also help B cells produce antibodies, two of the hallmarks of SLE pathology. In order to assess the role of IL-17 producing T cells in SLE, we used a mouse model of lupus. Indeed, we showed in this pilot study that IL-17 producing T cells accumulate in the spleen and lymph nodes of these mice and also infiltrate their kidneys. We further evaluated the role of IL-17 by culturing lymphocytes from lupus-prone mice in vitro with IL-23, a cytokine that sustains IL-17 responses, and then injected them in healthy but lymphocyte deficient mice. The recipient mice developed lupus-like disease suggesting a pathogenic role of IL-23 induced IL-17 producing T cells. In a different study we generated IL-23 receptor genetically deficient lupus-prone mice. These mice did not develop lupus. Taken together these results led us to hypothesize that IL-23 represents a key mediator of lupus pathogenesis. In this proposal we will test this hypothesis using lupus prone mice and lymphocytes from patients with SLE. Initially, we will test whether treatment of lupus-prone mice with an anti-IL-23 antibody can ameliorate lupus in mice at various stages of their disease course. We will then a. determine the exact source of IL-23 in lupus-prone mice; b. explore the signaling events that lead to the generation and maintenance of IL-17 producing cells in lupus; and c. unravel the mechanisms that IL-17 producing cells use to cause lupus. In the third aim, we will evaluate the role of IL-23 in the generation of pathogenic immune responses by both T and B cells in patients with SLE. These complementary murine and human studies will allow us to understand the role of IL-23 in the development of the abnormal immune response in lupus. The overall goal of this proposal is to provide the necessary rationale to introduce specific biologic agents that interfere with the IL-23/IL-17 pathway in the treatment of patients with SLE.

描述(申请人提供)：系统性红斑狼疮(SLE)是一种影响关节、皮肤和肾脏等许多器官的系统性自身免疫性疾病，其治疗基于非特异性免疫抑制药物，通常无效，并有非常显著的副作用。为了开发更特异、毒性更低的药物，我们需要更好地了解导致并随后维持SLE异常自身免疫反应的确切步骤。最近，在SLE患者的肾脏和外周血中发现了一种特殊的T细胞亚群，它表达促炎细胞因子IL-17。产生IL-17的细胞既可以诱导靶器官的局部炎症，也可以帮助B细胞产生抗体，这是SLE病理的两个特征。为了评估产生IL-17的T细胞在SLE中的作用，我们使用了狼疮小鼠模型。事实上，我们在这项初步研究中表明，产生IL-17的T细胞在这些小鼠的脾和淋巴结中积聚，并渗透到它们的肾脏。我们通过在体外用IL-23培养狼疮易感小鼠的淋巴细胞来进一步评估IL-17的作用，IL-23是一种支持IL-17反应的细胞因子，然后将它们注射到健康但淋巴细胞缺乏的小鼠中。受体小鼠出现狼疮样疾病，表明IL-23诱导产生IL-17的T细胞起致病作用。在另一项研究中，我们培育了IL-23受体基因缺陷的狼疮易感小鼠。这些小鼠没有发展成狼疮。综上所述，这些结果使我们假设IL-23是狼疮发病的关键介质。在这项建议中，我们将使用狼疮易感小鼠和SLE患者的淋巴细胞来验证这一假设。首先，我们将测试用抗IL-23抗体治疗狼疮易感小鼠是否可以改善处于病程不同阶段的小鼠的狼疮。然后，我们将A.确定狼疮易感小鼠中IL-23的确切来源；B.探索导致狼疮中产生和维持IL-17产生细胞的信号事件；以及C.揭示IL-17产生细胞用于引起狼疮的机制。在第三个目标中，我们将评估IL-23在SLE患者T和B细胞产生致病免疫反应中的作用。这些互补的小鼠和人类研究将使我们了解IL-23在狼疮异常免疫反应发展中的作用。这项提案的总体目标是为在SLE患者的治疗中引入干扰IL-23/IL-17途径的特定生物制剂提供必要的理论基础。