Impact of TNFa blockade on immune function in acute Kawasaki disease

点击翻译按钮获取中文摘要

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)