The role of interleukin 23 in lupus

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种影响许多器官（如关节、皮肤和肾脏）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，这些药物通常无效且具有非常显著的副作用。为了开发更有针对性的毒性更小的药物，我们需要更好地了解导致并维持SLE异常自身免疫反应的确切步骤。最近，一种表达促炎细胞因子IL-17的特定T细胞亚群已被证明存在于SLE患者的肾脏和外周血中。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病理的两个标志。为了评估产生IL-17的T细胞在SLE中的作用，我们使用狼疮小鼠模型。事实上，我们在这项初步研究中发现，产生IL-17的T细胞在这些小鼠的脾脏和淋巴结中积聚，并渗入肾脏。我们在体外用IL-23（一种维持IL-17反应的细胞因子）培养狼疮易感小鼠的淋巴细胞，然后将其注射到健康但淋巴细胞缺陷的小鼠中，进一步评估了IL-17的作用。受体小鼠出现狼疮样疾病，提示IL-23诱导产生IL-17的T细胞的致病作用。在另一项研究中，我们产生了IL-23受体基因缺陷的狼疮易感小鼠。这些老鼠没有患上狼疮。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。在这个提议中，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狼疮在其疾病病程的各个阶段。然后，我们将a.确定易患狼疮小鼠中IL-23的确切来源；b.探索导致狼疮中IL-17产生细胞产生和维持的信号事件；c.揭示产生IL-17的细胞导致狼疮的机制。在第三个目标中，我们将评估IL-23在SLE患者T细胞和B细胞产生致病性免疫反应中的作用。这些互补的小鼠和人类研究将使我们能够了解IL-23在狼疮异常免疫反应发展中的作用。本提案的总体目标是为引入干扰IL-23/IL-17通路的特异性生物制剂治疗SLE患者提供必要的理论依据。

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.