The decision to move forward with 3 clinical trials of interleukin-1 (IL-1) blockade for the treatment of acute Kawasaki disease (KD) is a case study in translational science. These trials were born, on the one hand, from transcriptome studies of host response during the acute disease coupled with animal model investigations of key immune signaling pathways and, on the other hand, out of clinical desperation to enhance treatment of patients with severe inflammation in the setting of acute KD. The convergence of laboratory science and clinical observations led to the clinical trials described herein and serves as a model for how such observations can be translated into new therapies. The successful translation of bench research into clinical practice requires physician scientists who understand both unmet clinical needs and experimental gaps in knowledge. In the case of KD, a self-limited vasculitis of unknown etiology and the most common cause of acquired heart disease in children, communication between research teams achieved the necessary coalescence of science and clinical medicine to rapidly translate experimental mouse data and human transcriptomic data into 3 separate clinical trials on 2 continents. What follows is a story of how research teams in Europe and the US capitalized on experimental findings to devise clinical trials to test a new paradigm: KD is a systemic inflammatory condition in which activation of the IL-1 signaling pathway is an essential driver of disease pathogenesis. The current understanding of KD is that an immunologic reaction is elicited in genetically susceptible hosts upon exposure to the KD trigger or triggers, which are thought to be stimuli that enter through the upper respiratory tract (1). Both mystery and controversy surround the exact nature of the trigger, with some groups advocating a novel virus and others suggesting an antigenic exposure without an infectious agent. The subset of children with KD who have damage to the coronary arterial wall (2–4) and aneurysms in these vessels comprise only 25% of the total population of KD-susceptible children (5). Therapy with intravenous immunoglobulin (IVIG) reduces the prevalence of aneurysms to 3–6%, and rates of aneurysms are highest among patients who do not become afebrile after the first dose of 2 gm/kg of IVIG (6, 7).

The mechanism by which IVIG reduces inflammation in the majority of patients is only now being elucidated despite the widespread clinical use of this treatment for more than 3 decades. In vitro studies have documented that IVIG increases IL-1 receptor antagonist (IL-1Ra) expression in human monocytes, which may be relevant in KD (8). Recent immunologic studies have established that secretion of IL-10 by tolerogenic myeloid dendritic cells (MDCs) and natural Treg (nTreg) cells is a critical event in down-regulation of inflammation in acute