Potential Role of IL-1B Therapies for Treatment of Vasculitis of Kawasaki Disease

IL-1B 疗法在治疗川崎病血管炎中的潜在作用

• 批准号: 8226576
• 负责人: Moshe Arditi
• 金额: $ 8.35万
• 依托单位: CEDARS-SINAI 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: 2012-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8226576
• 关键词: Acute; Aneurysm; Arteritis; Back; Blood Circulation; Blood Vessels; Bone Marrow; C57BL/6 Mouse; Cardiac; Caspase-1; Cell Wall; Cells; Child; Childhood; Chimera organism; Chronic; Clinical Trials; Coronary; Coronary artery; Data; Development; Disease; Effectiveness; Endothelial Cells; Goals; Grant; Heart Diseases; Hematopoietic; Human; Immune; Immune system; Immunomodulators; Inflammation; Inflammatory; Injection of therapeutic agent; Interleukin-1; Interleukin-12; Intraperitoneal Injections; Intravenous Immunoglobulins; Knockout Mice; Lactobacillus casei; Lesion; Literature; Mediator of activation protein; Modality; Modeling; Molecular; Morbidity - disease rate; Mucocutaneous Lymph Node Syndrome; Mus; Pathogenesis; Pathology; Patients; Play; Publishing; Receptor Signaling; Recombinants; Role; Signal Transduction; Stromal Cells; TLR2 gene; TLR4 gene; Testing; Therapeutic; Therapeutic Agents; Treatment Failure; Vasculitis; Wild Type Mouse; anakinra; base; cell type; cytokine; human data; human disease; inhibitor/antagonist; innovation; insight; mortality; mouse model; novel; prevent; receptor; receptor binding; stem; therapeutic effectiveness

DESCRIPTION (provided by applicant): Kawasaki disease (KD) is the most common cause of acquired cardiac disease and acute vasculitis in children in the developed world. The pathogenesis and molecular mechanisms are still unclear. The injection of Lactobacillus casei cell wall extract (LCCWE) to C57BL/6 mice causes a focal coronary arteritis that histopathologically mimics the coronary lesions observed in KD patients. Prior studies by our group and others suggest a key role of the immune system in this mouse model of KD. Using various knockout mice, we showed that LCCWE-induced coronary arteritis requires intact MyD88 and TLR2 but not TLR4 signaling (Circulation 2005). Since MyD88 is required for both the formation of pro-IL-12 (via NF:B activation) and for IL-1 receptor signaling, we propose to further characterize the role of the inflammatory cytokine IL-12 in the pathogenesis of coronary artery inflammation, the focus of this R03 application. Our prior findings together with recent published human data have questioned the role of IL-12 in recalcitrant human disease and in this model, and our recent preliminary studies now indicate that LCCWE does not induce coronary arteritis in IL-1R-/- mice and caspase-1-/- mice suggesting a major role for IL-12 in the pathogenesis of coronary arteritis. We propose studies with 2 Specific Aims to test the hypothesis that IL-12 plays a critical role in the LCCWE-induced mouse model of Kawasaki disease and novel treatments using inhibitors of IL-12 could provide valuable targeted therapies for human Kawasaki disease. In Specific Aim 1 we will determine the role of IL-12 for the development of LCCWE-induced coronary arteritis. We will give recombinant IL-12 back to caspase-1-/- mice and confirm the role of IL-12 . We will create bone marrow chimeras using donor and recipient combinations involving IL-1R-/- and wild-type mice to dissect the importance of IL-12 signaling in cells of hematopoietic origin versus stromal cells (i.e. endothelial cells). In Specific Aim 2 we will evaluate the effectiveness of immunomodulatory targeted anti-IL-1 therapeutic agents in this mouse model of KD, specifically the IL-1 receptor antagonist, Anakinra, and the IL-1 soluble decoy receptor, Rilonacept. These studies should provide innovative mechanistic insights into the cellular and molecular understanding of the vasculitis and coronary arteritis seen in this mouse model of Kawasaki Disease. This significant observation may result in the development of novel therapies to prevent the cardiac complications in human Kawasaki Disease. PUBLIC HEALTH RELEVANCE: This grant will investigate the role of IL-1 in a mouse model of coronary arteritis mimicking Kawasaki Disease, the most common cause of acquired cardiac disease in the developed world. The overall goal is to characterize the role of IL-1 and the therapeutic implications of anti-IL-1 therapies in this murine model, in order to support the use of these immunomodulatory treatments in human clinical trials to prevent the cardiac sequelae of Kawasaki Disease.

描述（由申请人提供）：川崎病（KD）是发达国家儿童获得性心脏病和急性血管炎的最常见原因。其发病机制和分子机制尚不清楚。向 C57BL/6 小鼠注射干酪乳杆菌细胞壁提取物 (LCCWE) 会引起局灶性冠状动脉炎，其组织病理学类似于川崎病患者中观察到的冠状动脉病变。我们小组和其他人之前的研究表明，免疫系统在这种川崎病小鼠模型中发挥着关键作用。使用各种基因敲除小鼠，我们发现 LCCWE 诱导的冠状动脉炎需要完整的 MyD88 和 TLR2，但不需要 TLR4 信号传导（Circulation 2005）。由于 MyD88 对于 IL-12 前体的形成（通过 NF:B 激活）和 IL-1 受体信号转导都是必需的，因此我们建议进一步表征炎症细胞因子 IL-12 在冠状动脉炎症发病机制中的作用，这是 R03 应用的重点。我们之前的研究结果以及最近发表的人类数据对IL-12在顽固性人类疾病和该模型中的作用提出了质疑，我们最近的初步研究表明，LCCWE不会在IL-1R-/-小鼠和caspase-1-/-小鼠中诱导冠状动脉炎，这表明IL-12在冠状动脉炎的发病机制中发挥着重要作用。我们提出了具有 2 个具体目标的研究，以检验 IL-12 在 LCCWE 诱导的川崎病小鼠模型中发挥关键作用的假设，并且使用 IL-12 抑制剂的新疗法可以为人类川崎病提供有价值的靶向治疗。在具体目标 1 中，我们将确定 IL-12 在 LCCWE 诱导的冠状动脉炎发展中的作用。我们将重组IL-12回输给caspase-1-/-小鼠并确认IL-12的作用。我们将使用涉及 IL-1R-/- 和野生型小鼠的供体和受体组合来创建骨髓嵌合体，以剖析造血源细胞与基质细胞（即内皮细胞）中 IL-12 信号传导的重要性。在具体目标 2 中，我们将评估免疫调节靶向抗 IL-1 治疗药物在 KD 小鼠模型中的有效性，特别是 IL-1 受体拮抗剂 Anakinra 和 IL-1 可溶性诱饵受体 Rilonacept。这些研究应该为川崎病小鼠模型中观察到的血管炎和冠状动脉炎的细胞和分子理解提供创新的机制见解。这一重要的观察结果可能会导致开发新的疗法来预防人类川崎病的心脏并发症。 公共健康相关性：这项拨款将研究 IL-1 在模拟川崎病的冠状动脉炎小鼠模型中的作用，川崎病是发达国家获得性心脏病的最常见原因。总体目标是在该小鼠模型中表征 IL-1 的作用以及抗 IL-1 疗法的治疗意义，以支持在人体临床试验中使用这些免疫调节疗法来预防川崎病的心脏后遗症。