Daniela Cihakova, MD, PhD

Therapy for Pediatric Cardiomyopathy by Targeting IFN-γ/PD-L1 Pathway
The Johns Hopkins University, Baltimore, MD
Daniela Cihakova, MD, PhD – $50,000

Pediatric cardiomyopathies are rare diseases with an annual incidence of 1.3 per 100,000. Dilated cardiomyopathy is the most common cardiomyopathy type. Children with dilated cardiomyopathy have poor outcomes with 46% of them dying or needing a heart transplant 5 years from diagnosis. About 30% of patients with myocarditis develop dilated cardiomyopathy. Currently, there is no treatment to protect myocarditis patients from dilated cardiomyopathy. In myocarditis animal models, a cytokine IFN-γ or IFN-γ receptor deficiency was found to cause severe viral and autoimmune myocarditis followed by rapid progression to dilated cardiomyopathy and death. It was discovered that IFN-γ is indispensable for the induction of programmed death-ligand 1 expression in cardiac endothelial cells but not in other cardiac stroma cells or cardiac resident immune cells. Programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis is a co-inhibitory pathway that induces energy in peripheral T cells. There is other evidence that the PD-1/PD-L1 pathway is important in myocarditis development, since cancer patients treated with drugs inhibiting this pathway can develop fatal myocarditis. This observation is supported by animal studies where blockade of PD-1/PD-L1 interaction led to spontaneous myocarditis development in mice. This study will address the regulatory capacity of IFN-γ and PD-1/PD-L1 axis to prevent progression of myocarditis to dilated cardiomyopathy in the pediatric population.