Effects of Intranasal Administration of Recombinant Murine Interferon-γ on Murine Acute Myocarditis Caused by Encephalomyocarditis Virus

Yamamoto, Norimi; Shibamori, Masafumi; Ogura, Motohiro; Seko, Yoshinori; Kikuchi, Mikio

doi:10.1161/01.cir.97.10.1017

Cited by 26 publications

(15 citation statements)

References 16 publications

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“…Our findings indicate that IFN-␥ exerts an important proinflammatory effect in the heart during MAV-1 myocarditis in neonatal mice and that inflammation induced by IFN-␥ signaling rather than direct antiviral effects of IFN-␥ may be important for survival. Similarly, IFN-␥ overexpression (13) or administration (45) ameliorates myocarditis in CVB3 and encephalomyocarditis virus models, respectively. However, this effect is likely due to the direct suppression of viral replication by IFN-␥ or IFN-␥-mediated activation of natural killer cells (46).…”

Section: Discussionmentioning

confidence: 99%

Proinflammatory Effects of Interferon Gamma in Mouse Adenovirus 1 Myocarditis

McCarthy

Procario

Twisselmann

et al. 2015

J Virol

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Adenoviruses are frequent causes of pediatric myocarditis. Little is known about the pathogenesis of adenovirus myocarditis, and the species specificity of human adenoviruses has limited the development of animal models, which is a significant barrier to strategies for prevention or treatment. We have developed a mouse model of myocarditis following mouse adenovirus 1 (MAV-1) infection to study the pathogenic mechanisms of this important cause of pediatric myocarditis. Following intranasal infection of neonatal C57BL/6 mice, we detected viral replication and induction of interferon gamma (IFN-␥) in the hearts of infected mice. MAV-1 caused myocyte necrosis and induced substantial cellular inflammation that was composed predominantly of CD3 ؉ T lymphocytes. Depletion of IFN-␥ during acute infection reduced cardiac inflammation in MAV-1-infected mice without affecting viral replication. We observed decreased contractility during acute infection of neonatal mice, and persistent viral infection in the heart was associated with cardiac remodeling and hypertrophy in adulthood. IFN-␥ is a proinflammatory mediator during adenovirus-induced myocarditis, and persistent adenovirus infection may contribute to ongoing cardiac dysfunction. IMPORTANCEStudying the pathogenesis of myocarditis caused by different viruses is essential in order to characterize both virus-specific and generalized factors that contribute to disease. Very little is known about the pathogenesis of adenovirus myocarditis, which is a significant impediment to the development of treatment or prevention strategies. We used MAV-1 to establish a mouse model of human adenovirus myocarditis, providing the means to study host and pathogen factors contributing to adenovirus-induced cardiac disease during acute and persistent infection. The MAV-1 model will enable fundamental studies of viral myocarditis, including IFN-␥ modulation as a therapeutic strategy.

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Section: Discussionmentioning

confidence: 99%

Proinflammatory Effects of Interferon Gamma in Mouse Adenovirus 1 Myocarditis

McCarthy

Procario

Twisselmann

et al. 2015

J Virol

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“…Intranasal administration of IFN-␥ suppresses viral replication and improves prognosis of murine myocarditis induced by encephalomyocarditis virus. 26 Transgenic expression of IFN-␥ in the pancreas protects mice from coxsackievirus B3-induced myocarditis. 27 The majority of cases of autoimmune myocarditis in humans are believed to be due to coxsackievirus infection and consist of viral and autoimmune phases that may be temporally separated or overlapping.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-12 Receptor/STAT4 Signaling Is Required for the Development of Autoimmune Myocarditis in Mice by an Interferon-γ–Independent Pathway

et al. 2001

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Background — Interleukin (IL)-12 exerts a potent proinflammatory effect by stimulating T-helper (Th) 1 responses. This effect is believed to be mediated primarily through the activation of STAT4 and subsequent production of interferon (IFN)-γ. Methods and Results — We examined the role of IL-12 receptor (IL-12R) signaling in the development of murine experimental autoimmune myocarditis (EAM) induced by cardiac myosin immunization. Both IL-12Rβ1–deficient mice and STAT4-deficient mice were resistant to the induction of myocarditis. Treatment with exogenous IL-12 exacerbated disease. We questioned whether IFN-γ is required for the disease-promoting activity of IL-12. On the contrary, we found that IFN-γ suppresses EAM. Lack of IFN-γ due to either depletion with an antibody or a genetic deficiency exacerbated myocarditis. Spleens from IFN-γ–deficient mice immunized with cardiac myosin showed increased cellularity; greater numbers of CD3+, CD4+, CD8+, and IL-2–producing cells; and heightened ability to produce cytokines on stimulation in vitro. Treatment of mice with recombinant IFN-γ suppressed the development of myocarditis. Conclusions — IL-12 / IL-12R/STAT4 signaling promotes the development of EAM. In contrast, IFN-γ plays a protective role. The disease-limiting effects of IFN-γ might be explained by its ability to control the expansion of activated T lymphocytes.

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“…Antiviral effects of IFN in an in vitro model of persistent enteroviral infection and its efficacy in preventing viral myocarditis in susceptible rodents are well known. 14,15,[32][33][34] However, because IFNs were administered before or simultaneously with enteroviral infections in these experiments, they do not adequately represent the situation in humans, in whom antiviral treatment is mostly feasible not before the stage of latent viral persistence. Apart from the direct virostatic effect of IFN-␤, immunomodulatory effects are induced that may suppress virus spreading and facilitate virus clearance.…”

Section: Searching For Novel Treatment Strategiesmentioning

confidence: 99%

“…Although efficacy of an immunomodulatory treatment of enteroviral infections was demonstrated in animal myocarditis models, reported applications in humans are anecdotal. 32,33,40,41 Successful treatment of myocarditis with antiviral agents has been reported in case reports. 42 A 6-month treatment with IFN-␣2a in 4 patients with enteroviral infection led to hemodynamic improvement in all patients, but virus was still detected in 2 of 4 patients.…”

Section: Searching For Novel Treatment Strategiesmentioning

confidence: 99%

Interferon-β Treatment Eliminates Cardiotropic Viruses and Improves Left Ventricular Function in Patients With Myocardial Persistence of Viral Genomes and Left Ventricular Dysfunction

et al. 2003

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Background— Viral infections are important causes of myocarditis and may induce cardiac dysfunction and finally lead to dilated cardiomyopathy. We investigated whether interferon (IFN)-β therapy is safe and may achieve virus clearance and prevent deterioration of left ventricular (LV) function in patients with myocardial virus persistence. Methods and Results— In this phase II study, 22 consecutive patients with persistence of LV dysfunction (history of symptoms, 44±27 months) and polymerase chain reaction–proven enteroviral or adenoviral genomes were treated with 18×10 6 IU/week IFN-β (Beneferon) subcutaneously for 24 weeks. Histological and immunohistological analysis of endomyocardial biopsies was used to characterize myocardial inflammation. LV diameters and ejection fraction were assessed by echocardiography and angiography, respectively. During the treatment period, IFN-β was well tolerated by all patients. No patient deteriorated. Clearance of viral genomes was observed in 22 of 22 of patients after antiviral therapy. Virus clearance was paralleled by a significant decrease of LV end diastolic and end systolic diameters, decreasing from 59.7±11.1 to 56.5±10.0 mm ( P <0.001) and 43.2±13.6 to 39.4±12.1 mm ( P <0.001), respectively. LV ejection fraction increased from 44.6±15.5% to 53.1±16.8% ( P <0.001). Conclusions— A 6 months, IFN-β treatment was safe in patients with myocardial enteroviral or adenoviral persistence and LV dysfunction and resulted in elimination of viral genomes (22 of 22 patients) and improved LV function (15 of 22 patients).

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Effects of Intranasal Administration of Recombinant Murine Interferon-γ on Murine Acute Myocarditis Caused by Encephalomyocarditis Virus

Cited by 26 publications

References 16 publications

Proinflammatory Effects of Interferon Gamma in Mouse Adenovirus 1 Myocarditis

Proinflammatory Effects of Interferon Gamma in Mouse Adenovirus 1 Myocarditis

Interleukin-12 Receptor/STAT4 Signaling Is Required for the Development of Autoimmune Myocarditis in Mice by an Interferon-γ–Independent Pathway

Interferon-β Treatment Eliminates Cardiotropic Viruses and Improves Left Ventricular Function in Patients With Myocardial Persistence of Viral Genomes and Left Ventricular Dysfunction

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