Lethal Autoimmune Myocarditis in Interferon-γ Receptor–Deficient Mice

Eriksson, Urs; Kurrer, Michael; Bingisser, Roland; Eugster, Hans-Pietro; Saremaslani, Parvin; Folláth, Ferenc; Marsch, Stephan; Widmer, U

doi:10.1161/01.cir.103.1.18

Cited by 99 publications

(60 citation statements)

References 12 publications

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“…IFN-g has been shown to be a downregulatory cytokine, as evidenced by exacerbated myocarditis in IFN-gR knockout (KO), IFN-g KO, and T-bet KO mice (9,53,54). In contrast, Th17 cells have recently been implicated in the pathogenesis of various types of autoimmune diseases (reviewed in Ref.…”

Section: Discussionmentioning

confidence: 99%

Suppressor of Cytokine Signaling 1 DNA Administration Inhibits Inflammatory and Pathogenic Responses in Autoimmune Myocarditis

Tajiri

Imanaka‐Yoshida

Matsubara

et al. 2012

The Journal of Immunology

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Myocarditis and subsequent dilated cardiomyopathy are major causes of heart failure in young adults. Myocarditis in humans is highly heterogeneous in etiology. Recent studies have indicated that a subgroup of myocarditis patients may benefit from immune-targeted therapies, because autoimmunity plays an important role in myocarditis as well as contributing to the progression to cardiomyopathy and heart failure. Suppressor of cytokine signaling (SOCS) 1 plays a key role in the negative regulation of both TLR- and cytokine receptor-mediated signaling, which is involved in innate immunity and subsequent adaptive immunity. In this study, we investigated the therapeutic effect of SOCS1 DNA administration on experimental autoimmune myocarditis (EAM) in mice. EAM was induced by s.c. immunization with cardiac-specific peptides derived from α myosin H chain in BALB/c mice. In contrast to control myocarditis mice, SOCS1 DNA-injected mice were protected from development of EAM and heart failure. SOCS1 DNA administration was effective for reducing the activation of autoreactive CD4+ T cells by inhibition of the function of Ag-presenting dendritic cells. Our findings suggest that SOCS1 DNA administration has considerable therapeutic potential in individuals with autoimmune myocarditis and dilated cardiomyopathy.

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Section: Discussionmentioning

confidence: 99%

Suppressor of Cytokine Signaling 1 DNA Administration Inhibits Inflammatory and Pathogenic Responses in Autoimmune Myocarditis

Tajiri

Imanaka‐Yoshida

Matsubara

et al. 2012

The Journal of Immunology

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“…IFN-g neutralization strongly influenced the Th1/Th2 balance but did not affect the disease outcome, indicating that a Th1-dominated immune response is not necessarily associated with disease severity in EAMG [32]. Unexpected disease-ameliorating effects by IFN-g have also been observed in EAE [33][34][35][36], lethal autoimmune myocarditis [37] and collageninduced arthritis [38].…”

Section: Discussionmentioning

confidence: 99%

Dendritic cells exposed in vitro to TGF-beta1 ameliorate experimental autoimmune myasthenia gravis

et al. 2002

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“…We first looked for a short-lived, soluble mediator and analyzed nitrite levels reflecting NO production in supernatants of APC/T cell/CD11b ϩ monocyte cocultures. NO had been shown to mediate suppression of T cells (15). As illustrated in Fig.…”

Section: Cd11b ϩ Monocytes Release No Suppressing T Cell Proliferatiomentioning

confidence: 97%

“…IFN-␥R Ϫ/Ϫ mice have been described previously (15). All mice were backcrossed to the BALB/c strain for Ͼ12 generations and were used at 6 -8 wk of age.…”

Section: Micementioning

confidence: 99%

“…These latter findings further support the idea that IL-17 directly accounts for disease development and point toward a negative regulatory role of IFN-␥ and Th1 differentiation in the EAM model. Indeed, and in contrast to wild-type mice, IFN-␥R Ϫ/Ϫ and IFN-␥ Ϫ/Ϫ mice show an exacerbated and progressive disease course (11,15,16). These observations were attributed to either impaired apoptosis of CD25 ϩ CD4 ϩ regulatory T cells (17) or to NO-mediated T cell growth arrest (15).…”

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confidence: 99%

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CD11b+ Monocytes Abrogate Th17 CD4+ T Cell-Mediated Experimental Autoimmune Myocarditis

Valaperti

Marty

Kania

et al. 2008

The Journal of Immunology

129

120

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Experimental autoimmune myocarditis (EAM) represents a Th17 T cell-mediated mouse model of postinflammatory heart disease. In BALB/c wild-type mice, EAM is a self-limiting disease, peaking 21 days after α-myosin H chain peptide (MyHC-α)/CFA immunization and largely resolving thereafter. In IFN-γR−/− mice, however, EAM is exacerbated and shows a chronic progressive disease course. We found that this progressive disease course paralleled persistently elevated IL-17 release from T cells infiltrating the hearts of IFN-γR−/− mice 30 days after immunization. In fact, IL-17 promoted the recruitment of CD11b+ monocytes, the major heart-infiltrating cells in EAM. In turn, CD11b+ monocytes suppressed MyHC-α-specific Th17 T cell responses IFN-γ-dependently in vitro. In vivo, injection of IFN-γR+/+CD11b+, but not IFN-γR−/−CD11b+, monocytes, suppressed MyHC-α-specific T cells, and abrogated the progressive disease course in IFN-γR−/− mice. Finally, coinjection of MyHC-α-specific, but not OVA-transgenic, IFN-γ-releasing CD4+ Th1 T cell lines, together with MyHC-α-specific Th17 T cells protected RAG2−/− mice from EAM. In conclusion, CD11b+ monocytes play a dual role in EAM: as a major cellular substrate of IL-17-induced inflammation and as mediators of an IFN-γ-dependent negative feedback loop confining disease progression.

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Lethal Autoimmune Myocarditis in Interferon-γ Receptor–Deficient Mice

Abstract: Our data provide evidence that IFN-gamma protects mice from lethal autoimmune myocarditis by inducing the expression of inducible nitric oxide synthase followed by the downregulation of T-cell responses.

Cited by 99 publications

References 12 publications

Suppressor of Cytokine Signaling 1 DNA Administration Inhibits Inflammatory and Pathogenic Responses in Autoimmune Myocarditis

Suppressor of Cytokine Signaling 1 DNA Administration Inhibits Inflammatory and Pathogenic Responses in Autoimmune Myocarditis

Dendritic cells exposed in vitro to TGF-beta1 ameliorate experimental autoimmune myasthenia gravis

CD11b+ Monocytes Abrogate Th17 CD4+ T Cell-Mediated Experimental Autoimmune Myocarditis

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