Impact of TNFa blockade on immune function in acute Kawasaki disease

描述（由申请人提供）：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。在发热后最初10天内静脉注射高剂量免疫球蛋白（IVIG, 2g /kg）并联合高剂量阿司匹林，可使对IVIG有反应的患者发生冠状动脉瘤的风险降低至3-5%。然而，大约15-30%的儿童对IVIG有耐药性，并在IVIG输注后48小时内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。由于TNFa在KD发病机制中的核心作用，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，将英夫利昔单抗联合IVIG用于急性KD的主要治疗。该试验由FDA孤儿病项目通过RO1资助机制资助，目前正在两个临床站点（Clintrials.gov标识符NCT00760435）招募患者。我们假设英夫利昔单抗可以通过三种不同的机制更快地解决炎症和改善冠状动脉结局：1)阻断巨噬细胞和树突状细胞特定亚群的成熟；2)限制促炎CD8+ T细胞和T辅助（Th） 1细胞（包括记忆T细胞）的效应功能；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，肌醇1,4,5-三磷酸激酶C （ITPKC）通过钙调神经磷酸酶/NFAT途径影响t细胞活化的功能多态性将影响C等位基因杂合的患者炎症反应的程度。因此，我们建议在临床试验中研究KD患者的先天和适应性免疫反应，并将这些研究与临床反应和患者在ITPKC位点的基因型联系起来。

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)