Impact of TNFa blockade on immune function in acute Kawasaki disease

描述（由申请方提供）：KD是一种病因不明的急性血管炎，是美国和日本儿童获得性心脏病的主要原因。虽然急性疾病会自行消退，但20-25%未经治疗的儿童会发生冠状动脉永久性损伤。在发热后的前10天内给予高剂量静脉注射免疫球蛋白（IVIG，2 g/kg）联合高剂量阿司匹林可将IVIG反应患者的冠状动脉瘤风险降低至3-5%。然而，大约15-30%的儿童对IVIG有抵抗力，并且在IVIG输注后48小时内会出现复发性发热和临床症状。这些患者发生冠状动脉异常的风险增加，需要额外的抗炎治疗。受TNF α在KD发病机制中的核心作用的启发，我们启动了一项随机、双盲、安慰剂对照、双中心的III期临床试验，即英夫利昔单抗联合IVIG用于急性KD的主要治疗。该试验由FDA孤儿病项目通过RO 1资助机制资助，目前正在两个临床研究中心招募患者（Clintrials.gov标识符NCT 00760435）。我们推测，英夫利西单抗的给药将通过三种不同的机制导致炎症的更快消退和冠状动脉预后的改善：1）阻断巨噬细胞和树突状细胞的特定亚群的成熟; 2）限制促炎性CD 8 + T细胞和辅助性T细胞（Th）1细胞（包括记忆性T细胞）的效应子功能; 3）促进外周诱导的调节性T细胞的扩增和分化。我们进一步假设，在肌醇1，4，5-三磷酸3-激酶C（ITPKC），通过钙调磷酸酶/NFAT途径影响T细胞活化的功能多态性将影响患者的炎症反应的大小杂合子的C等位基因。因此，我们建议研究参加临床试验的KD患者的先天性和适应性免疫应答，并将这些研究与ITPKC基因座的临床应答和患者基因型相关联。 这里提出的研究是重要的，因为他们解决了潜在的机制，对治疗有潜在生命威胁的疾病的儿童。他们是创新的，因为他们利用正在进行的临床试验的患者来回答关于TNFa在KD发病机制中的作用的基本问题，这些问题只能通过比较两个治疗组中患者的“免疫快照”来回答。这些辅助研究将利用经验丰富的KD研究者和成熟的细胞免疫学家的专业知识，生成有关KD两种不同治疗方法的免疫学后果的新信息。与公共卫生的相关性：在发达国家，川崎是获得性小儿心脏病的主要原因，如果不及时治疗，25%的患者会导致严重的冠状动脉损伤。该提案旨在了解不同疗法如何调节免疫系统以及患者遗传学如何塑造免疫反应。这些研究可能会导致新的治疗方法，将防止心脏损伤。(End摘要）

DESCRIPTION (provided by applicant): KD is an acute vasculitis of unknown etiology that is the leading cause of acquired heart disease in children in the United States and Japan. Although the acute illness resolves spontaneously, permanent damage to the coronary arteries occurs in 20-25% of untreated children. High dose intravenous immunoglobulin (IVIG, 2 g/kg) administered within the first 10 days after fever onset in combination with high dose aspirin reduces the risk of coronary artery aneurysms to 3-5% in IVIG-responsive patients. However, approximately 15-30% of children are resistant to IVIG and will develop recrudescent fever and clinical signs within 48 hours following their IVIG infusion. These patients are at increased risk of developing coronary artery abnormalities and require additional anti-inflammatory therapy. Motivated by the central role of TNFa in KD pathogenesis, we initiated a randomized, double-blind, placebo-controlled, two-center Phase III clinical trial of infliximab plus IVIG for the primary treatment of acute KD. The trial is funded by the FDA Orphan Disease program through an RO1 funding mechanism and is currently enrolling patients at the two clinical sites (Clintrials.gov identifier NCT00760435). We postulate that the administration of infliximab will result in more rapid resolution of inflammation and improved coronary artery outcome through three different mechanisms: 1) Blocking the maturation of specific subsets of macrophages and dendritic cells; 2) Limiting the effector function of pro-inflammatory CD8+ T cells and T helper (Th) 1 cells, including memory T-cells; 3) Facilitating the expansion and differentiation of peripherally induced regulatory T cells. We further postulate that a functional polymorphism in the inositol 1,4,5-triphosphate 3-kinase C (ITPKC) that affects T-cell activation through the calcineurin/NFAT pathway will influence the magnitude of the inflammatory response in patients heterozygous for the C allele. Accordingly we propose to study the innate and adaptive immune response in KD patients enrolled in the clinical trial and correlate these studies with clinical response and patient genotype at the ITPKC locus. The studies proposed here are significant because they address the mechanisms underlying response to treatment in children with a potentially life-threatening disease. They are innovative because they leverage patients from an ongoing clinical trial to answer fundamental questions about the role of TNFa in KD pathogenesis that can only be answered by comparing "immunological snapshots" of patients in the two treatment arms. These ancillary studies will capitalize on the expertise of a seasoned KD investigator and a well-establish cellular immunologist to generate new information on the immunologic consequences of two different treatments for KD. Relevance to Public Health: Kawasaki disease is the leading cause of acquired pediatric heart disease in developed countries, which if left untreated, results in serious coronary artery damage in 25% of patients. This proposal seeks to understand how the immune system is modulated by different therapies and how patient genetics shapes the immune response. These studies may lead to new treatments that will prevent heart damage. (End of Abstract)