Impact of TNFa blockade on immune function in acute Kawasaki disease

描述(申请人提供)：KD是一种原因不明的急性脉管炎，是美国和日本儿童获得性心脏病的主要原因。虽然这种急性疾病会自动痊愈，但在未经治疗的儿童中，有20%-25%的儿童冠状动脉会受到永久性损害。在发热后头10天内给予大剂量静脉注射免疫球蛋白(IVIG，2g/kg)，并联合使用大剂量阿司匹林，可将IVIG反应患者的冠状动脉动脉瘤风险降低至3-5%。然而，大约15%-30%的儿童对IVIG具有抵抗力，并将在注射IVIG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。出于TNFa在KD发病机制中的核心作用，我们启动了英夫利昔单抗联合IVIG治疗急性KD的随机、双盲、安慰剂对照、双中心III期临床试验。该试验由FDA孤儿疾病项目通过RO1资助机制提供资金，目前正在两个临床站点(Clintrials.gov标识符NCT00760435)招募患者。我们推测，英夫利昔单抗可通过三种不同的机制：1)阻断巨噬细胞和树突状细胞亚群的成熟；2)限制促炎CD8+T细胞和辅助性T细胞(Th)1细胞的效应功能，包括记忆T细胞；3)促进外周诱导的调节性T细胞的扩增和分化，从而更快地缓解炎症并改善冠状动脉预后。我们进一步推测，通过钙调神经磷酸酶/NFAT途径影响T细胞激活的肌醇1，4，5-三磷酸3-激酶C(ITPKC)功能多态性将影响C等位基因杂合子患者的炎症反应的程度。因此，我们建议研究参加临床试验的KD患者的先天和获得性免疫反应，并将这些研究与临床反应和ITPKC基因座的患者基因型相关联。 这里提出的研究意义重大，因为它们解决了患有一种潜在威胁生命的疾病的儿童对治疗的潜在反应机制。它们具有创新性，因为它们利用正在进行的临床试验中的患者来回答有关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患者的“免疫快照”来回答。这些辅助研究将利用一位经验丰富的KD研究人员和一位久负盛名的细胞免疫学家的专业知识，以产生关于两种不同治疗KD的免疫学后果的新信息。与公共卫生相关：在发达国家，川崎病是后天性儿童心脏病的主要原因，如果不加以治疗，25%的患者会导致严重的冠状动脉损害。这项建议试图了解免疫系统是如何被不同的治疗方法调节的，以及患者的遗传学是如何塑造免疫反应的。这些研究可能会带来预防心脏损伤的新疗法。(摘要结束)

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)