Myocarditis is an important cause of sudden death in up to 20% of young adults and frequently progresses to dilated cardiomyopathy, which accounts for up to 1 in 25 cases of heart failure;yet, there is no specific and effective treatment for thi devastating condition. Strong evidence supports that progression of acute (e.g. viral) myocarditis to chronic myocarditis and ensuing dilated cardiomyopathy are most frequently mediated by an autoimmune assault against heart tissue;however, for unknown reasons immunosuppressive treatments are not very effective and current treatment focuses on managing clinical symptoms and providing supportive care. In our preliminary studies we found that immunosuppressive glucocorticoid (GC) hormone treatment of macrophage migration inhibitory factor (MIF) knockout mice completely prevented the progression of experimental autoimmune myocarditis (EAM), an animal model of myocarditis, to dilated cardiomyopathy (DCM). Therefore, we will test in the present application inhibitors of MIF in combination with GC treatment as novel therapeutic approach for this disease. The rational for these studies is that MIF has been shown to promote EAM. Furthermore, MIF stimulates IL-17 production by pathogenic T cells, which is a critical cytokine for induction of EAM. Importantly, MIF is unique i that it is the only known proinflammatory cytokine induced by GCs and to subsequently counter-regulate GC- mediated immunosuppression. Since treatment of MIF knockout (MIF-/-) mice with Dexamethasone (Dex) completely prevented progression of EAM to DCM (our preliminary results), we hypothesize that MIF plays a critical role in resistance to immunosuppressive treatment and that inhibiting this cytokine in combination with GCs in myocarditis patients could represent a novel treatment approach and major therapeutic advance. We will test our central hypothesis with the following specific aims:
Aim 1. To determine the efficacy of MIF inhibitors in preventing resistance to GC treatment in EAM and progression to dilated cardiomyopathy. We will test the hypothesis that inhibition of MIF with anti-MIF mAb or small molecule MIF inhibitors will prevent DCM in Dex treated BALB/c wild-type (wt) mice analogous to MIF-/- mice.
Aim 2. To determine the key mechanism(s) how MIF promotes resistance to Dex in EAM and progression to DCM. We will test the hypothesis that MIF inhibits GC treatment effects in EAM and progression to DCM by modulating chemokines/chemokine receptors and homing molecules guiding recruitment of inflammatory cells and Prominin-1/CD133+ myeloid precursor cells to the heart and their differentiation into fibroblasts and DCM. We expect that the proposed studies will provide important information that is currently not available and which will have significant and lasting impact on research and treatment of myocarditis and DCM.
Myocarditis and dilated cardiomyopathy are devastating conditions affecting relatively young people in the prime of their lives;despite the medical importance of these diseases, no specific and effective treatment strategies have been developed. Based on our striking preliminary results we propose to test in the present application the clinical efficacy of MIF inhibitors in preventing progression of experimental autoimmune myocarditis (EAM) to dilated cardiomyopathy as a preclinical proof-of-principle model. Furthermore, we will identify key molecules modulated by MIF to antagonize immunosuppressive treatment with glucocorticoids to provide the conceptual framework for rational development of next-generation therapeutics.
|Bloom, Joshua; Metz, Christine; Nalawade, Saisha et al. (2016) Identification of Iguratimod as an Inhibitor of Macrophage Migration Inhibitory Factor (MIF) with Steroid-sparing Potential. J Biol Chem 291:26502-26514|
|Raphael, Itay; Nalawade, Saisha; Eagar, Todd N et al. (2015) T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine 74:5-17|