Our long-term goal is to understand pathogenesis of chronic myocarditis, a disease that has a grim prognosis with more than 50% of patients dying or needing a heart transplant within 5 years. We will use a murine model of experimental autoimmune myocarditis (EAM), where the disease is induced in susceptible mice by immunization with cardiac myosin or its myocarditogenic peptide in adjuvant. Based on our findings that IFN-y knockout (KO) mice and IL-13 KO mice develop severe myocarditis, we hypothesize that IFN-y and IL-13 are beneficial cytokines in myocarditis. We chose to focus on these two mediators because they may lead to novel therapies for myocarditis and other inflammatory cardiovascular diseases.
The specific aims of this proposal are: SA1: To determine the influence of IFN-y upon apoptotic pathways in autoreactive lymphocytes in EAM. Since IFN-y KO mice have fewer apoptotic CD4+ T lymphocytes than wild type controls, we hypothesize that IFN-y limits the survival of autoreactive T cells, thus protecting the heart from severe myocarditis. We will test the effect of manipulation of IFN-y dependent pathways of apoptosis in vitro and in vivo on the severity of myocarditis. SA2: To study the role of IL-13 in the progression of EAM. Our preliminary results show that IL-13 also has a protective role in EAM. IL-13 shares a common receptor with IL-4 as well as the STAT6 dependent signaling pathway, yet it has an opposite effect in EAM. We will study the pathogenesis of IL-13 by (i) blocking the cytokine at different times during the disease; (ii) determining cellular origin and kinetics of IL-13 during myocarditis; (iii) testing the hypothesis that IL-13 utilizes a new receptor or a new signaling pathway. SA3: To evaluate the therapeutic effects of recombinant (r) IFN-y and/or rIL-13 in different myocarditis models. In humans multiple antigens and epitope were identified as targets of autoimmune responses. Therefore, we will examine the efficiency of the recombinant cytokine treatment in different myocarditis models: (i) myocarditogenic peptide induced EAM; (ii) whole myosin induced EAM; (iii) virus-induced myocarditis; and (iv) troponin l-induced EAM. Relevance to Public Health: There is a great need for improved therapies that could slow down, stop, or even reverse inflammatory changes in the heart. We propose to broaden our knowledge of the pathogenesis of myocarditis, in order to rationalize new biologic approaches to treatment. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067290-06
Application #
7210605
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Massicot-Fisher, Judith
Project Start
2001-04-01
Project End
2010-03-30
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
6
Fiscal Year
2007
Total Cost
$444,524
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Rose, Noel R (2016) Viral myocarditis. Curr Opin Rheumatol 28:383-9
Rose, Noel R (2015) Molecular mimicry and clonal deletion: A fresh look. J Theor Biol 375:71-6
Rose, Noel R (2014) Learning from myocarditis: mimicry, chaos and black holes. F1000Prime Rep 6:25
Barin, Jobert G; Baldeviano, G Christian; Talor, Monica V et al. (2013) Fatal eosinophilic myocarditis develops in the absence of IFN-? and IL-17A. J Immunol 191:4038-47
Chen, P; Baldeviano, G C; Ligons, D L et al. (2012) Susceptibility to autoimmune myocarditis is associated with intrinsic differences in CD4(+) T cells. Clin Exp Immunol 169:79-88
Barin, Jobert G; Baldeviano, G Christian; Talor, Monica V et al. (2012) Macrophages participate in IL-17-mediated inflammation. Eur J Immunol 42:726-36
Barin, Jobert G; Rose, Noel R; Ciháková, Daniela (2012) Macrophage diversity in cardiac inflammation: a review. Immunobiology 217:468-75
Rose, Noel R (2011) Critical cytokine pathways to cardiac inflammation. J Interferon Cytokine Res 31:705-10
Hedayat, Mona; Mahmoudi, Mohammad Jafar; Rose, Noel R et al. (2010) Proinflammatory cytokines in heart failure: double-edged swords. Heart Fail Rev 15:543-62
Barin, Jobert G; Talor, Monica V; Baldeviano, G Christian et al. (2010) Mechanisms of IFN? regulation of autoimmune myocarditis. Exp Mol Pathol 89:83-91

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