Kawasaki disease (KD) is the most common cause of acquired cardiac disease and acute vasculitis in children in the developed world. The pathogenesis and molecular mechanisms are still unclear. The injection of Lactobacillus casei cell wall extract (LCCWE) to C57BL/6 mice causes a focal coronary arteritis that histopathologically mimics the coronary lesions observed in KD patients. Prior studies by our group and others suggest a key role of the immune system in this mouse model of KD. Using various knockout mice, we showed that LCCWE-induced coronary arteritis requires intact MyD88 and TLR2 but not TLR4 signaling (Circulation 2005). Since MyD88 is required for both the formation of pro-IL-12 (via NF:B activation) and for IL-1 receptor signaling, we propose to further characterize the role of the inflammatory cytokine IL-12 in the pathogenesis of coronary artery inflammation, the focus of this R03 application. Our prior findings together with recent published human data have questioned the role of IL-12 in recalcitrant human disease and in this model, and our recent preliminary studies now indicate that LCCWE does not induce coronary arteritis in IL-1R-/- mice and caspase-1-/- mice suggesting a major role for IL-12 in the pathogenesis of coronary arteritis. We propose studies with 2 Specific Aims to test the hypothesis that IL-12 plays a critical role in the LCCWE-induced mouse model of Kawasaki disease and novel treatments using inhibitors of IL-12 could provide valuable targeted therapies for human Kawasaki disease.
In Specific Aim 1 we will determine the role of IL-12 for the development of LCCWE-induced coronary arteritis. We will give recombinant IL-12 back to caspase-1-/- mice and confirm the role of IL-12 . We will create bone marrow chimeras using donor and recipient combinations involving IL-1R-/- and wild-type mice to dissect the importance of IL-12 signaling in cells of hematopoietic origin versus stromal cells (i.e. endothelial cells).
In Specific Aim 2 we will evaluate the effectiveness of immunomodulatory targeted anti-IL-1 therapeutic agents in this mouse model of KD, specifically the IL-1 receptor antagonist, Anakinra, and the IL-1 soluble decoy receptor, Rilonacept. These studies should provide innovative mechanistic insights into the cellular and molecular understanding of the vasculitis and coronary arteritis seen in this mouse model of Kawasaki Disease. This significant observation may result in the development of novel therapies to prevent the cardiac complications in human Kawasaki Disease.
This grant will investigate the role of IL-1 in a mouse model of coronary arteritis mimicking Kawasaki Disease, the most common cause of acquired cardiac disease in the developed world. The overall goal is to characterize the role of IL-1 and the therapeutic implications of anti-IL-1 therapies in this murine model, in order to support the use of these immunomodulatory treatments in human clinical trials to prevent the cardiac sequelae of Kawasaki Disease.