Kawasaki disease (KD) is an acute febrile illness and systemic vasculitis that predominantly afflicts children and is the leading cause of acquired heart disease among this age group. Coronary artery aneurysms (CAA) develop in 25% of untreated children with KD, leading to ischemic heart disease, myocardial infarction, and long-term cardiovascular complications during adulthood. While high dose IVIG treatment plus aspirin reduces CAA incidence from 25% to 5%, up to 30% of KD patients are non-responsive to IVIG and have a higher risk of developing CAA. Therefore, discovery of novel and more effective treatments to prevent the cardiovascular complications (e.g. CAA) of KD is one of the highest research priorities. A well-accepted mouse model of KD is available which reproduces the coronary vasculitis, myocarditis, immunopathologic features of the cardiovascular lesions observed in KD patients. Recent data from genetic studies as well as this experimental mouse model have converged on the critical role of IL-1R signaling in the pathogenesis of KD lesions. As a result, two clinical trials have begun examining the efficacy of an IL-1R inhibitor in IVIG-resistant KD patients. However, emerging data suggests that inhibition of IL-1R can significantly increase risk of infection. Therefore, strategies to block alternative or upstream pathways may be beneficial in KD and eliminate the increased risk of infection associated with IL-1R antagonism. As our central hypothesis, we envision that IL-1 play a critical role in CA stenosis by promoting the pathogenic conversion of smooth muscle cells (SMCs) into obstructive myofibroblasts and that the IL-23/IL-17 axis concomitantly acts with IL-1 to propagate chronic inflammation in the vasculature. Despite the significance of IL-1 in KD, it's exact role is unclear. SMCs are known to migrate and proliferate in the vasculature, leading to vessel narrowing and risk of ischemia or infarction. IL-1R signaling in SMCs has been shown to enhance these behaviors and thus we believe that IL-1 acts on SMCs to promote coronary stenosis in KD.
In Aim 1, we will use genetic techniques to ablate IL- 1R signaling in SMCs, which we hypothesize will reduce vascular inflammation and abrogate vessel stenosis in our mouse model of KD. Aberrant IL-17 and IL-23 activities have been associated with autoimmune and autoinflammatory diseases. After discovering that both cytokines are elevated in our mouse model as well in published KD cohorts, we now propose to examine their significance.
In Aim 2 we will examine if deficiency of IL-17 or IL-23 impairs induction of KD and corroborate results with antibody-mediated depletion in wild type mice. If successful, this proposal will identify IL-17 and/or IL-23 as therapeutic targets in KD and further our understanding of IL-1's role in vascular pathogenesis by connecting IL-1 activity to vessel stenosis. In addition, if IL-17/23 neutralization proves beneficial, translation to human will be streamlined as antibodies against both cytokines are already in use in the clinic.
Kawasaki Disease (KD) vasculitis is the leading cause of acquired heart disease among children and recent studies suggest a key role for the inflammatory molecule IL-1 in this vasculitic disease. In the current proposal we will identify novel cellular mechanisms that are involved the IL-1-mediated tissue responses and additional inflammatory molecules during KD, using an experimental mouse model that mimics human disease, in order to improve and develop novel therapeutic approaches for this potentially serious and even fatal cardiac disease.
