Impact of TNFa blockade on immune function in acute Kawasaki disease

TNFa阻断对急性川崎病免疫功能的影响

基本信息

批准号：
8438506
负责人：
JANE C BURNS
金额：
$ 32.76万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-15 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8438506
关键词：
Acute Address Affect Aftercare Alleles Ancillary Study Aneurysm Anti-Inflammatory Agents Anti-inflammatory Antigen Presentation Aspirin Automobile Driving Autopsy Blood specimen Burn injury CD8B1 gene Calcineurin Cell Culture Techniques Cell Maturation Cells Cellular Immunology Child Childhood Clinical Clinical Trials Clinical trial protocol document Cloning Coronary artery Cytotoxic T-Lymphocytes DNA Dendritic Cells Developed Countries Disease Dose Double-Blind Method Enrollment Etiology Fever Funding Funding Mechanisms Future Genes Genetic Genetic Polymorphism Genotype Harvest Heart Heart Diseases Hour Human Immune response Immune system Immunologics Immunologist Infiltration Inflammation Inflammatory Inflammatory Response Infusion procedures Inositol Interferons Intravenous Immunoglobulins Japan Lead Left Life Link Lymphokines Measures Mediator of activation protein Molecular Monoclonal Antibodies Mucocutaneous Lymph Node Syndrome NFAT Pathway Nature Outcome Outcome Measure Pathogenesis Patients Peripheral Blood Mononuclear Cell Phase Phase III Clinical Trials Phenotype Phosphotransferases Placebo Control Placebos Plasma Population Predisposition Public Health Randomized Rare Diseases Regulatory T-Lymphocyte Relative Risks Reporting Research Personnel Resistance Resolution Risk Role Sampling Seasons Shapes Specific qualifier value Stratification T memory cell T-Cell Activation T-Cell Activation Pathway T-Lymphocyte TNF gene Testing Therapeutic Effect Tissues United States Vasculitis abstracting arm base clinical research site cohort cytokine design immune activation immune function immunological status improved infliximab innovation interleukin-15 receptor macrophage monocyte peripheral blood prevent primary outcome programs response treatment response tripolyphosphate

项目摘要

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)

描述（由申请人提供）：KD是一种未知病因的急性血管炎，是美国和日本儿童获得性心脏病的主要原因。尽管急性疾病会自发解决，但在20-25％的未经治疗的儿童中，冠状动脉的永久损害发生。高剂量静脉免疫球蛋白（IVIG，2 g/kg）在发烧发作后的前10天内与高剂量阿司匹林结合使用，将冠状动脉动脉瘤的风险降低到IVIG反应性患者的3-5％。但是，大约15-30％的儿童对IVIG具有抵抗力，并将在IVIG输注后的48小时内发展出重发烧和临床体征。这些患者患冠状动脉异常的风险增加，需要额外的抗炎疗法。由TNFA在KD发病机理中的核心作用的动机，我们启动了一项随机，双盲，安慰剂对照的，两中性的III期临床试验，对英夫利昔单抗加IVIG进行了急性KD的主要治疗方法。该试验由FDA孤儿病计划通过RO1资助机制资助，目前正在两个临床部位（Clintrials.gov识别剂NCT00760435）招募患者。我们假设，英夫利昔单抗的给药将通过三种不同的机制更快地消除炎症，并改善冠状动脉结局：1）阻止巨噬细胞和树突状细胞的特定亚群的成熟； 2）限制促炎性CD8+ T细胞和T辅助器（Th）1个细胞的效应子功能，包括记忆T细胞； 3）促进周围诱导的调节性T细胞的膨胀和分化。我们进一步假设，肌醇1,4,5-三磷酸3-激酶C（ITPKC）中的功能性多态性会通过钙调蛋白/NFAT途径影响T细胞激活，将影响C等位基因杂合子的患者炎症反应的大小。因此，我们建议研究参加临床试验的KD患者的先天和适应性免疫反应，并将这些研究与ITPKC基因座的临床反应和患者基因型相关联。此处提出的研究很重要，因为它们解决了潜在威胁生命疾病的儿童对治疗的反应的基础机制。它们具有创新性，因为他们利用正在进行的临床试验中的患者来回答有关TNFA在KD发病机理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研究者的专业知识和一位良好的细胞免疫学家，以产生有关KD两种不同治疗方法的免疫学后果的新信息。与公共卫生有关：川崎疾病是发达国家获得的小儿心脏病的主要原因，如果不进行治疗，则导致25％的患者导致严重的冠状动脉损害。该建议旨在了解免疫系统如何通过不同的疗法调节，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，以防止心脏损伤。（抽象的结尾）