Long-term follow up of patients with dilated heart muscle disease treated with human leucocytic interferon alpha or thymic hormones initial results.

Mirić, Milutin; Vasiljević, Jovan; Bojić, Milovan; Popović, Zoran B.; Keserović, N; Milan, Pesic

doi:10.1136/hrt.75.6.596

Cited by 61 publications

(32 citation statements)

References 14 publications

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“…Interferon-␣ benefit was described in a case study 117 and in a single-center, randomized trial comparing its efficacy to placebo or thymomodulin. 118 Although mortality did not differ, LVEF rose significantly more in the treatment than the placebo group. Interferon-␤ has also been shown to produce benefit in a phase II, single-center study of patients with PCR-detected enteroviral or adenoviral genome on endomyocardial biopsy.…”

Section: Treatmentmentioning

confidence: 95%

Myocarditis

2006

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Section: Treatmentmentioning

confidence: 95%

Myocarditis

2006

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“…On the basis of the results from both virus-and CM-induced models of myocarditis, IFN-␥ may be an appropriate candidate. Miric et al 30 showed the efficacy of IFN-␣ treatment in patients with biopsy-proven myocarditis and dilated cardiomyopathy.…”

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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“…It can be fatal in infants and, although usually resolved in adults, can progress to chronic myocarditis and/or dilated cardiomyopathy with concomitant cardiac failure (11,28). Recent clinical studies have indicated that alpha interferon (IFN-␣) (11,21,35,36) and IFN-␤ (29) can reduce the severity of viral myocarditis, inhibiting viral replication and improving cardiac function. Nonetheless, viral myocarditis remains a disease without reliable treatment, and the prognosis remains poor for more than half of patients presenting with clinical symptoms (45).…”

mentioning

confidence: 99%

Basal Expression Levels of IFNAR and Jak-STAT Components Are Determinants of Cell-Type-Specific Differences in Cardiac Antiviral Responses

Zurney¹,

Howard

Sherry

2007

J Virol

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Viral myocarditis is an important human disease, and reovirus-induced murine myocarditis provides an excellent model system for study. Cardiac myocytes, like neurons in the central nervous system, are not replenished, yet there is no cardiac protective equivalent to the blood-brain barrier. Thus, cardiac myocytes may have evolved a unique antiviral response relative to readily replenished cell types, such as cardiac fibroblasts. Our previous comparisons of these two cell types revealed a conundrum: reovirus T3D induces more beta-interferon (IFN-␤) mRNA in cardiac myocytes, yet there is a greater induction of IFN-stimulated genes (ISGs) in cardiac fibroblasts. Here, we investigated possible underlying molecular determinants. We found that greater basal expression of IFN-␤ in cardiac myocytes results in greater basal activated nuclear STAT1 and STAT2 and greater basal ISG mRNA expression and provides greater basal antiviral protection relative to cardiac fibroblasts. Conversely, cardiac fibroblasts express greater basal IFN-␣/␤ receptor 1 (IFNAR1) and greater basal cytoplasmic Jak1, Tyk2, STAT2, and IRF9, leading to a greater increase in reovirus T3D-or IFN-induced nuclear activated STAT1 and STAT2 and greater induction of ISGs for a greater IFN-induced antiviral protection relative to cardiac myocytes. Our results suggest that high basal IFN-␤ expression in cardiac myocytes prearms this vulnerable, nonreplenishable cell type, while high basal expression of IFNAR1 and latent Jak-STAT components in adjacent cardiac fibroblasts renders these cells more responsive to IFN and prevents them from inadvertently serving as a reservoir for viral replication and spread to cardiac myocytes. These studies provide the first indication of an integrated network of cell-type-specific innate immune components for organ protection.

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Long-term follow up of patients with dilated heart muscle disease treated with human leucocytic interferon alpha or thymic hormones initial results.

Abstract: (Heart 1996;75:596-601)

Cited by 61 publications

References 14 publications

Myocarditis

Myocarditis

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

Basal Expression Levels of IFNAR and Jak-STAT Components Are Determinants of Cell-Type-Specific Differences in Cardiac Antiviral Responses

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