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

描述(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脉管炎的最常见原因。其发病机制和分子机制尚不清楚。将干酪乳杆菌细胞壁提取物(LCCWE)注射到C57BL/6小鼠体内，可引起与KD患者冠状动脉病变相似的局灶性冠脉炎。我们小组和其他人之前的研究表明，免疫系统在这种KD小鼠模型中起着关键作用。使用不同的基因敲除小鼠，我们发现LCCWE诱导的冠脉炎需要完整的MyD88和TLR2信号，但不需要TLR4信号(循环2005)。由于MyD88对前IL-12的形成(通过核因子：B激活)和IL-1受体信号传递都是必需的，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应用的焦点。我们之前的发现和最近发表的人类数据一起质疑了IL-12在顽固性人类疾病和这个模型中的作用，我们最近的初步研究表明，LCCWE不会在IL-1R-/-小鼠和caspase-1-/-小鼠中诱导冠脉炎，这表明IL-12在冠脉炎的发病机制中发挥了重要作用。我们提出了两个特定目的的研究，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，使用IL-12抑制剂的新疗法可能为人类川崎病提供有价值的靶向治疗。在特定的目标1中，我们将确定IL-12在LCCWE诱导的冠脉炎发生中的作用。我们将重组IL-12回馈给caspase-1-/-小鼠，并确认IL-12的作用。我们将使用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IL-12信号在造血细胞与基质细胞(即内皮细胞)中的重要性。在特定的目标2中，我们将评估免疫调节靶向抗IL-1治疗药物在这种KD小鼠模型中的有效性，特别是IL-1受体拮抗剂Anakinra和IL-1可溶性诱骗受体Rilonacept。这些研究应该为了解川崎病小鼠模型中的脉管炎和冠脉炎的细胞和分子机制提供创新的见解。这一重要的观察结果可能导致开发新的治疗方法来预防人类川崎病的心脏并发症。 公共卫生相关性：这笔赠款将研究IL-1在模仿川崎病的冠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。总体目标是确定IL-1在这一小鼠模型中的作用以及抗IL-1治疗的治疗意义，以便支持在人类临床试验中使用这些免疫调节治疗来预防川崎病的心脏后遗症。

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.