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：
8230550
负责人：
JANE C BURNS
金额：
$ 38.24万
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 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8230550
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 Orphan Disease 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 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）：川崎病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。尽管这种急性疾病会自行消退，但 20-25% 未经治疗的儿童会出现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）并结合高剂量阿司匹林，可将 IVIG 反应性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 具有抵抗力，并会在输注 IVIG 后 48 小时内出现复热和临床症状。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，我们发起了一项随机、双盲、安慰剂对照、两中心的 III 期临床试验，英夫利昔单抗联合 IVIG 用于急性 KD 的主要治疗。该试验由 FDA 孤儿病计划通过 RO1 资助机制资助，目前正在两个临床中心招募患者（ClinTrials.gov 标识符 NCT00760435）。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退炎症并改善冠状动脉的结局：1）阻止特定巨噬细胞和树突状细胞亚群的成熟； 2) 限制促炎性CD8+ T细胞和辅助性T细胞（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 3-激酶 C (ITPKC) 的功能多态性通过钙调神经磷酸酶/NFAT 途径影响 T 细胞活化，从而影响 C 杂合子患者的炎症反应程度。等位基因。因此，我们建议研究参加临床试验的川崎病患者的先天性和适应性免疫反应，并将这些研究与临床反应和患者 ITPKC 基因座基因型相关联。这里提出的研究意义重大，因为它们解决了患有潜在危及生命的疾病的儿童对治疗的反应机制。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 在川崎病发病机制中的作用的基本问题，而这些问题只能通过比较两个治疗组中患者的“免疫学快照”来回答。这些辅助研究将利用经验丰富的 KD 研究人员和成熟的细胞免疫学家的专业知识，生成有关两种不同 KD 治疗的免疫学后果的新信息。与公共健康的相关性：川崎病是发达国家儿童获得性心脏病的主要原因，如果不及时治疗，会导致 25% 的患者出现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影响免疫反应。这些研究可能会带来预防心脏损伤的新疗法。（摘要完）