Neutralization of endogenous tumor necrosis factor ameliorates the severity of myosin-induced myocarditis.

Smith, Stacy C.; Allen, Paul M.

doi:10.1161/01.res.70.4.856

Cited by 113 publications

(45 citation statements)

References 37 publications

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“…Deficiencies in IFN-γ and its receptor were found to lead to exacerbated, progressive, and fatal EAM [6,22,38]. IFN-γ-and IFN-γ-induced iNOS were also shown to limit the expansion of α-MyHC-reactive CD4 + T cells in EAM [18,34,39]. Finally, T-bet−/− mice, which are impaired in Th1 differentiation, exhibited enhanced disease severity [40].…”

Section: Discussionmentioning

confidence: 99%

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Absence of nonhematopoietic MHC class II expression protects mice from experimental autoimmune myocarditis

et al. 2015

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Experimental autoimmune myocarditis (EAM) is a CD4 + T-cell-mediated model of human inflammatory dilated cardiomyopathies.Heart-specific CD4 + T-cell activation is dependent on autoantigens presented by MHC class II (MHCII) molecules expressed on professional APCs. In this study, we addressed the role of inflammation-induced MHCII expression by cardiac nonhematopoietic cells on EAM development. EAM was induced in susceptible mice lacking inducible expression of MHCII molecules on all nonhematopoietic cells (pIV−/− K14 class II transactivator (CIITA) transgenic (Tg) mice) by immunization with α-myosin heavy chain peptide in CFA. Lack of inducible nonhematopoietic MHCII expression in pIV−/− K14 CIITA Tg mice conferred EAM resistance. In contrast, cardiac pathology was induced in WT and heterozygous mice, and correlated with elevated cardiac endothelial MHCII expression. Control mice with myocarditis displayed an increase in infiltrating CD4 + T cells and in expression of IFN-γ, which is the major driver of nonhematopoietic MHCII expression. Mechanistically, IFN-γ neutralization in WT mice shortly before disease onset resulted in reduced cardiac MHCII expression and pathology. These findings reveal a previously overlooked contribution of IFN-γ to induce endothelial MHCII expression in the heart and to progress cardiac pathology during myocarditis. Keywords: CD4 + T cells Experimental autoimmune myocarditis (EAM) Endothelial antigen presentation Interferon-γ MHC class IIAdditional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Prof. Hans Acha-Orbea e-mail: hans.acha-orbea@unil.ch C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2016. 46: 656-664 Immunomodulation 657 IntroductionInflammatory dilated cardiomyopathy is a common cause of heart failure in young patients and often results from myocarditis in predisposed individuals [1]. CD4 + T-cell-mediated experimental autoimmune myocarditis (EAM) is a model for inflammatory heart disease and is induced in mice either by immunization with α-myosin heavy chain (α-MyHC) derived peptides emulsified in CFA [2][3][4] or by vaccination with α-MyHC-loaded activated dendritic cells (DCs) [5]. Typically, both Th1 and Th17 cells are induced during the course of EAM. It is assumed that both of these subsets mediate myocarditis as mice deficient in either interleukin 17 (IL-17) or interferon γ (IFN-γ) develop cardiac pathology [6,7]. Remarkably, heart-specific autoimmune inflammation has been shown to be a consequence of impaired central tolerance induction to α-MyHC during T-cell development in mice and in humans [8]. CD4 + T-cell-orchestrated immune responses are driven by MHC class II (MHCII) mediated antigen presentation. MHCII is primarily expressed on professional APCs. Cardiac APCs were suggested to present cardiac myosin before the onset of cardiac pathology [9], and DCs, the major APC subset able to initiate primary immune responses, were shown to be critical for ...

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Section: Discussionmentioning

confidence: 99%

“…In fact, MHCII expression can be observed on cardiac nonhematopoietic cells during myocarditis in both humans and rodents [13][14][15]. Induction of MHC class II molecules depends critically on IFN-γ, which is dominantly expressed during myocarditis [16][17][18]. Interestingly, IFN-γ plays a dual role in myocarditis.…”

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confidence: 99%

Absence of nonhematopoietic MHC class II expression protects mice from experimental autoimmune myocarditis

et al. 2015

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“…27,28 Thus one might have anticipated that expression of the human TNFRII-Fc would blunt myocarditis in the baboon heart. However, as serum sTNFRII levels only reached B3 times the baseline levels of baboon sTNFRII, we suggest that insufficient TNFRII-Fc serum levels were achieved to block this TNF-dependent process.…”

Section: Direct Injection Of Aav-2 Into Baboon Hearts Cf Mctiernan Et Almentioning

confidence: 99%

Myocarditis following adeno-associated viral gene expression of human soluble TNF receptor (TNFRII-Fc) in baboon hearts

et al. 2007

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Sequestration of tumor necrosis factor-a (TNFa) by TNFreceptor immunoglobulin G (IgG)-Fc fusion proteins can limit heart failure progression in rodent models. In this study we directly injected an adeno-associated viruses (AAV)-2 construct encoding a human TNF receptor II IgG-Fc fusion protein (AAV-TNFRII-Fc) into healthy baboon hearts and assessed virally encoded gene expression and clinical response. Adult baboons received direct cardiac injections of AAV-TNFRII-Fc (B5 Â 10 12 viral/genomes/baboon) or an equivalent dose of AAV-2 empty capsids, and were analyzed after 5 or 12 weeks. Viral genomes were restricted to the myocardium, and routine analyses (blood cell counts, clinical chemistries) remained unremarkable. Echocardiograms were unchanged but electrocardiograms revealed marked ST-and T-wave changes consistent with myocarditis only in baboons receiving AAV-TNFRII-Fc. TNFRII serum levels peaked at B3 times the baseline levels at 1-2 weeks postinjection and subsequently declined to baseline levels. TNFRII-Fc protein and transcripts were detected in the heart at harvest. After AAV injection, anti-AAV-2 antibody levels increased in all baboons, while anti-TNFRII-Fc could not be detected. Baboons that received AAV-TNFRII-Fc developed myocardial infiltrates including CD8+ cells. Thus, a cellular immune response to cardiac delivery of AAV encoding foreign proteins may be an important consideration for AAV-based cardiac gene therapy.

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“…97 In A/J mice, monoclonal antibody neutralization of TNF-␣ reduced the severity of myocarditis whereas anti-IFN-␥ increased the severity of disease. 98 TNF-␣ is believed to be produced by heartinfiltrating macrophages in the rat model of myocarditis and to be important in cardiovascular diseases. 99 It has been reported that the lack of TNF-␣ receptor (TNF-R) p55 gene expression could interfere with either lymphocyte activation or target organ susceptibility.…”

Section: Influence Of Cytokines On Myocarditis and Th1/ Th2 Immune Rementioning

confidence: 99%

Cardiac Myosin and the TH1/TH2 Paradigm in Autoimmune Myocarditis

Cunningham

2001

The American Journal of Pathology

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Neutralization of endogenous tumor necrosis factor ameliorates the severity of myosin-induced myocarditis.

Cited by 113 publications

References 37 publications

Absence of nonhematopoietic MHC class II expression protects mice from experimental autoimmune myocarditis

Absence of nonhematopoietic MHC class II expression protects mice from experimental autoimmune myocarditis

Myocarditis following adeno-associated viral gene expression of human soluble TNF receptor (TNFRII-Fc) in baboon hearts

Cardiac Myosin and the TH1/TH2 Paradigm in Autoimmune Myocarditis

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