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J Am Coll Cardiol, 2000; 36:1979-1984
© 2000 by the American College of Cardiology Foundation
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EXPERIMENTAL STUDY

Immunoglobulin treatment ameliorates murine myocarditis associated with reduction of neurohumoral activity and improvement of extracellular matrix change

Chiharu Kishimoto, MD, PhD*, Nami Takamatsu, RN*, Hiroshi Kawamata, MD{dagger}, Hiromichi Shinohara, MD, PhD{ddagger} and Hiroshi Ochiai, MD, PhD{ddagger}

* Second Department of Internal Medicine, Faculty of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan
{dagger} Department of Oriental Medicine, Faculty of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan
{ddagger} Department of Human Science, Faculty of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan

Manuscript received December 28, 1999; revised manuscript received June 15, 2000, accepted July 25, 2000.

Reprint requests and correspondence: Dr. Chiharu Kishimoto, The Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
kkishi{at}kuhp.kyoto-u.ac.jp


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES

We examined effects of immunoglobulin on murine myocarditis induced by encephalomyocarditis virus, not pathogenic to humans, and analyzed the plasma cytokine and catecholamine levels and the changes of the extracellular matrix with or without the treatment.

BACKGROUND

We have previously shown that immunoglobulin therapy suppressed murine coxsackievirus B3 myocarditis by an antiviral effect. However, it is not yet determined whether beneficial effects of immunoglobulin for myocarditis are due to antiviral effects or to other unknown effects.

METHODS

Antiviral activity of human immunoglobulin (Polyglobin-N) against encephalomyocarditis virus was determined in vitro. Immunoglobulin (1 g/kg/day) was administered intraperitoneally to the virus-infected mice daily for two weeks, beginning simultaneously with virus inoculation in experiment I and on day 14 after virus inoculation in experiment II.

RESULTS

Antiviral activity of immunoglobulin could not be detected in the assay of a plaque-reduction method in vitro. The in vivo study showed that immunoglobulin administration ameliorated both myocardial necrosis with interstitial fibrin deposition in experiment I and interstitial fibrosis with the improvement of ventricular remodeling in experiment II by the reduction of plasma catecholamines, interferon-alpha, and soluble intercellular adhesion molecule-1.

CONCLUSIONS

Immunoglobulin therapy could suppress myocarditis associated with the improvement of extracellular matrix changes by the reduction of neurohumoral activity.

Abbreviations and Acronyms
  EMC virus = encephalomyocarditis virus
  E = epinephrine
  IFN-{gamma} = interferon-{gamma}
  NE = norepinephrine
  PFU = plaque-forming units
  sICAM-1 = soluble intercellular adhesion molecule-1
  VERO cells = African green monkey kidney cells

The therapeutic efficacy of immunoglobulin in inflammatory and autoimmune diseases has been reported (1–5). The prophylactic administration of immunoglobulin was reported to be of clinical value against some virus infections, and this effect was due to the capacity of immunoglobulin to neutralize the viruses. The successful treatment of idiopathic thrombocytopenic purpura with immunoglobulin appears to result from the blockade of Fc receptors (5) The rapid effect in children with Kawasaki disease may be due to the neutralization of a microbial toxin by immunoglobulin (3) that binds nonspecifically to certain viable regions of the T-cell-antigen receptor.

Infiltration of the myocardium with inflammatory cells occurs during infection with a variety of viruses (6,7). Myofiber necrosis is an important feature of this lesion. Viral myocarditis is considered a cause of dilated cardiomyopathy (6,7). Histologically, myocarditis is manifested by foci of myocyte necrosis with interstitial inflammation, whereas cardiomyopathy is characterized by diffuse interstitial fibrosis, myocyte hypertrophy and an absence of acute inflammation (8). Much attention has recently been focused on changes of the extracellular matrix in myocardial diseases (9,10). It is well known that fiber-forming proteins are of two functional types: mainly structural (collagens and laminin) and mainly adhesive (fibrin, fibronectin and laminin) (11). All the matrix proteins are secreted locally by cells in contact with the matrix. The extracellular matrix was thought to serve as a relatively inert frame to stabilize the physical structure of myocytes. But it is now clear that the matrix plays an active role in regulating the behavior of the cells in myocarditis and other myocardial diseases (11).

We have previously demonstrated (12) that immunoglobulin therapy suppressed murine myocarditis induced by coxsackievirus B3, the most cardiotropic agent in humans. However, it is not yet determined whether the beneficial effects are due to antiviral effects or other, unknown effects. Thus, in the present study, we examined the effects of immunoglobulin on experimental murine myocarditis induced by encephalomyocarditis virus (13), which may not infect humans. We also analyzed the plasma catecholamine and cytokine levels, the most sensitive markers for myocardial dysfunction, and the changes of the extracellular matrix with and without the treatment.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
In vitro study.   Immunoglobulin (Polyglobin-N) was kindly supplied by Bayer Co., Ltd., Japan. Antiviral activity against encephalomyocarditis (EMC) virus was assayed by a plaque-reduction method, as previously described (12). Serially diluted sterile solution of immunoglobulin was incubated with 100 plaque-forming units (PFU) of EMC virus at 37°C for 1 h. The reaction was stopped at 4°C for 30 min. The sample was added to confluent monolayers of VERO (African green monkey kidney) cells in six-well plastic plates. After two days of incubation at 37°C, the cells were fixed with acetic acid and methanol and stained with crystal violet; then the plaques were counted. Plaque formation was expressed as a percentage of the number of control plaques (12).

In vivo study.   Infection protocol
The virus stock of EMC virus prepared in cultures of VERO cells in Eagle’s minimum essential medium (13). Virus suspensions were centrifuged after the cytopathic effect had developed, and the viral stock had a titer of >109 PFU/ml determined in tissue cultures.

Four-week-old male, inbred, certified virus-free DBA/2 mice (Shizuoka Laboratory Animal Center) were used. The animals were inoculated intraperitoneally with 0.1 ml virus suspension containing 10 PFU. The studies were approved by the institution’s Animal Care and Use Committee.

Treatment protocol
Immunoglobulin was administered intraperitoneally daily; the actual dose in each experiment was calculated from the mouse weight at the beginning of the experiment. As determined from previous studies (1,2,12), the dose of immunoglobulin used was 1 g/kg/day.

Experiment I
Sixty mice were randomized to two groups that received either no treatment (n = 30) or treatment with immunoglobulin (n = 30). Mice in the untreated group were injected intraperitoneally with 0.1 ml saline during the treatment period.

Treatment was begun simultaneously with the virus inoculation and was given for 14 days. The mice were observed daily, and necropsy was performed immediately on those found dead. Seven mice in each group were killed on day 7 for virological study and for an age-matched study of cardiac pathology. Accordingly, the survival study covered 23 mice in each of the two groups. Mice surviving until the end of the treatment period were killed and the organs were processed for pathological study.

Two additional control groups consisted of uninfected mice treated for 14 days with saline (n = 3) and with immunoglobulin (n = 3).

Experiment II
Mice surviving until 14 days after virus inoculation (n = 40) were randomized to either of two groups: no treatment (n = 20) or treatment with immunoglobulin (n = 20). Treatment was given for 14 days, i.e., until 28 days after virus inoculation. Five mice in each group were killed on day 21 for cardiac pathology. Accordingly, the survival study covered 15 mice in each of the two groups. The mice were observed daily, and necropsy was carried out on those that died during the course of the experiment. At the end of the treatment period, the same procedure as in experiment I was performed.

Two additional control groups consisted of age-matched uninfected mice treated for 14 days with saline (n = 3) and with immunoglobulin (n = 3) in parallel with the study protocol.

Pathological study
Hearts were snap-frozen or embedded in paraffin. The heart sections were stained with hematoxylin-eosin to identify active myocardial necrosis and with Masson’s trichrome to identify repairing fibrosis. Fibrin was demmstrated in situ by direct immunoperoxidase staining with the use of an antibody to mouse fibrin (14).

The histological sections were examined and the extent of inflammatory lymphocyte infiltration and active myocardial necrosis was evaluated semiquantitatively on a scale of 1+ to 4+. In addition, fibrin deposition and fibrosis were quantified using computer-assisted image analysis as previously described (14). In brief, microscopic images were studied with an Olympus BX50 microscope (Tokyo, Japan) equipped with a video camera (Olympus ICD-740-1) connected to a color video monitor. A digitized tablet was used and an image analysis software package was used for morphometric analysis.

To avoid postmortem changes and to match the time course, pathological studies were performed only on mice euthanized on days 7, 14, 21 and 28.

Virological study
For the infectivity assay, portions of the heart were weighed and homogenized aseptically. After a 15-min centrifugation at 1,500 g, virus titers in the supernatants were determined by a plaque assay method as previously described (12,14).

Catecholamine assay
Plasma catecholamines (norepinephrine and epinephrine) were quantitated using reverse-phase high-pressure liquid chromatography with electrochemical detection. Plasma was deproteinized with 1.0 N HCL and centrifuged at 18,000 g for 10 min at 4°C. The resulting perchloric acid extracts were frozen at –80°C until analysis could be performed.

Cytokine assay
Plasma interferon-gamma (IFN-{gamma}) and soluble intercellular adhesion molecule –1 (sICAM-1) were determined using antibody-sandwich enzyme-linked immunosorbent assay.

Statistical analysis
Student t test for unpaired observation and chi-square analysis with Yates’ correction were used to evaluate differences in the study variables. A p value <0.05 was considered statistically significant.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
In vitro study.   The percent plaque formation was 92.9 ± 9.3% at an immunoglobulin concentration of 10–3.0 mg/ml, 93.0 ± 10.6% at 10–2.0mg/ml, 94.4 ± 9.5% at 10–1.0mg/ml, and 97.6 ± 6.3% at 100 mg/ml (each n = 5). There was no correlation between PFU and the immunoglobulin concentrations. Thus, immunoglobulin (Polyglobin-N) does not contain a significant amount of antibodies against EMC virus.

In vivo study.   Mortality
In experiment I, the survival rate of the immunoglobulin-treated group was significantly higher (p < 0.05) than that of the untreated control group. Survival rate on day 14 in each group was as follows: control group 43.5% (10/23) and immunoglobulin group 78.3% (18/23). In experiment II, the survival rate of the immunoglobulin-treated group was higher (p < 0.05) compared with that of controls. Survival rate on day 28 in each group was as follows: control group 60.0% (9/15) and immunoglobulin group 93.3% (14/15).

There were no deaths throughout the treatment period in either uninfected (immunoglobulin-treated or untreated) group in experiments I and II.

Cardiac pathology (Table 1, Figure 1)
In experiment I on days 7 and 14, both cellular infiltration and myocardial necrosis were significantly less severe in the immunoglobulin-treated group compared with the untreated group. In experiment II on days 21 and 28, both scores in the immunoglobulin-treated group were lower than those of the untreated group.


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  		Table 1 Cardiac Pathology

 


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  		Figure 1 Photominographs showing representative abnormalities of fibrin deposition and myocardial fibrosis in heart of a mouse with myocarditis in Experiment I (day 14). Interstitial fibrin deposition (A, arrows) and fibrosis (B, blue) in areas of myocardial necrosis in untreated group was more severe than in immunoglobulin-treated group (C, D). A, C = Immunoperoxidase stain for fibrin; B, D = Masson’s trichrome stain for fibrosis: A, B, C, D x120.

 
In experiments I and II, fibrin deposition was significantly less in the treated than in the control groups. In addition, fibrosis was less severe in the treated than in the control groups in both experiments.

There was no abnormal finding in the myocardium in each uninfected (immunoglobulin or untreated) group in experiments I and II.

Myocardial virus titers
Myocardial virus titers of immunoglobulin-treated mice were not statistically different from those of controls in experiments I and II (data not shown).

Catecholamine levels (Table 2)
Norepinephrine and epinephrine were significantly lower in the immunoglobulin-treated than in the untreated groups in experiments I and II. Catecholamine levels were significantly greater in the virus-infected mice than in the uninfected (control) mice (data not shown).


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  		Table 2 Neurohumoral Data

 
Cytokines levels (Table 2)
In experiments I and II, IFN-{gamma} and sICAM-1 were significantly lower in the immunoglobulin-treated than in the untreated groups.


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
This study showed that immunoglobulin treatment sufficiently ameliorated murine EMC viral myocarditis associated with reduction of plasma neurohumoral factors and improvement of extracellular matrix remodeling. The in vitro study showed the absence of neutralizing anti-EMC viral antibodies in the immunoglobulin used in this study. Thus, immunoglobulin could suppress EMC viral myocarditis, not by an antiviral effect, but by neurohumoral modification.

Role of immunoglobulin therapy.   The role of immunoglobulin in the therapy of myocarditis or acute dilated cardiomyopathies is not fully understood (15–18). Although idiopathic dilated cardiomyopathy is a heterogenous disorder, most patients are suspected of sharing a similar viral/autoimmune pathogenesis (8,19,20) and may benefit from immune modulatory therapy.

It is possible that immunoglobulin administration may alter immune responses, thus leading to a decrease in cardiac inflammation. The accepted mechanism of action is reticuloendothelial system blockade (1,2). Reticuloendothelial system blockade implies that high concentrations of immunoglobulin could prevent antigen presentation and stimulation of immune responses by several mechanisms. Polyclonal immunoglobulin may bind to Fc receptors on macrophages and prevent internalization of the antigens. Exogenous proteins may occupy phagocytic vesicles to the exclusion of autoantigens, thus inhibiting autoimmune processes. An overabundance of immunoglobulin peptides may competitively prevent autoantigen peptides from binding to relevant major histocompatibility class I or II molecules. Polyclonal immunoglobulin-treated macrophages may show deficiencies in inflammatory cytokine secretion (1,2).

Myocardial damage in myocarditis.   Numerous studies are being performed to elucidate the mechanisms of myocardial damage in myocarditis. Increasing evidence suggests that cytotoxic T cells (21), neurohumoral factors (22), inflammatory cytokines (23) and free radicals, possibly generated by infiltrating cells in the myocardium, play a significant role, separately or together, in the development of myocardial damage and dysfunction in addition to the primary damage caused by viral infection.

A direct connection between viral myocarditis and cardiomyopathy in humans has remained elusive (19). Studies in experimental animals have provided direct evidence to support this causal relationship and have brought us progressively closer to understanding some of the mechanisms whereby viral infection in the heart may trigger specific pathologic and immunologic responses (6,12,14,20–24). The experimental studies have documented the late development of myocardial fibrosis (9,10). However, the mechanisms responsible for this cardiac remodeling are unknown. Fibrin gels, when placed in the subcutaneous tissue of animals, elicit an angiogenetic and connective tissue response characterized by the formation of new blood vessels and the immigration of macrophages and fibroblasts, followed by the local synthesis of collagen and the deposition of collagen matrix (9,10). Extravasated fibrin may function as a template for the deposition of collagen during healing of the inflammation (24,25).

Immunoglobulin therapy in myocarditis.   Our previous study demonstrated that immunoglobulin therapy suppresses coxsackievirus B3 myocarditis by transferring the neutralizing antibody into the host in the acute stage, because human immunoglobulin contains the antibody against coxsackievirus B3, which is most common in humans (12). The present study was performed to evaluate mechanisms of immunoglobulin other than its neutralizing activity against viruses, because EMC virus is an enterovirus of the family Picornaviridae (13) and not pathogenic to humans. The results showed that immunoglobulin therapy could suppress EMC virus myocarditis not by EMC virus neutralizing activity but by the reduction of plasma catecholamines, IFN-{gamma}, and sICAM-1.

The findings of the present study have shown that immunoglobulin ameliorated EMC viral myocarditis via its effect on neurohumoral factors in the period of congestive heart failure (experiment II) and in the early stage (experiment I). Although we neither examined the pathology of the central nervous system nor detected viruses in the brain, the possibility of involvement of the central nervous system by a cardiotropic EMC virus used in this study may be low (13). Therefore, we consider that the activation of the sympathetic system was due to severe heart failure; subsequent immunoglobulin injection decreases plasma catecholamines, suggesting that immunoglobulin exerts its cardioprotective effect through sympathetic modulating actions.

Neurohumoral activation in heart failure.   The response to immunoglobulin appeared to be mediated by the sympathetic nervous system. The involvement of the sympathetic nervous system in heart failure caused by myocarditis has been addressed in number of earlier studies. For example, in animals with congestive heart failure caused by myocarditis, a relative limitation of the sympathetic activity might be present. In addition, studies in other models have implicated the involvement of catecholamines and the sympathetic nervous system (26). In the present study, neurohumoral activation was used as a clinical marker for congestive heart failure, and thus the observed effects on catecholamines by immunoglobulin administration are indirect.

The reduction of IFN-{gamma} and sICAM-1 by immunoglobulin administration was reported as a therapeutic possible mechanism in some inflammatory diseases, because immunoglobulin itself contains antibodies against cytokines (1,2). Also, suppression of cytokine-dependent T-cell proliferation by immunoglobulin treatment in vitro and in inflammatory disorders was demonstrated (27–29).

In a number of pathologic processes that result in fibrosis, such as wound healing and the generation of tumor stroma, extravascular fibrin deposition precedes collagen formation or fibrosis. In these processes, fibrin gel with inflammatory cytokines, i.e., IFN-{gamma} and sICAM-1, serves as a provisional matrix for angiogenesis, inflammatory cell and fibroblast migration, and subsequently fibrosis (11,24,25). We have already investigated interstitial fibrin deposition and myocardial fibrosis in a murine model in which myocarditis was caused by another cardiotropic virus, coxsackievirus B3 (14). It was reported that elevated plasma catecholamines and cytokines in heart failure may increase or change capillary permeability, which in turn triggers the extravasation of fibrin into the interstitium (12,24–26). The improvement of connective tissue abnormalities by immunoglobulin treatment demonstrated in the present study may be due, in part, to the suppressions of increased capillary permeability.

Study limitations.   In this study, the virus was isolated only by a conventional biological method instead of with the polymerase chain reaction. Accordingly, the possibility of the so-called persistent virus infection could not be completely excluded in experiment II.

Conclusions.   Immunoglobulin therapy could suppress myocarditis not only by anticardiotopic viral effects but also by anti-inflammatory effects associated with the reduction of plasma catecholamines as well as IFN-{gamma} and sICAM-1. This leads to the improvement of the structural changes of extracellular matrix.


   Acknowledgments
 
We thank Bayer Co., Ltd., Japan, for their kind gift of human immunoglobulin preparations.


   Footnotes
 
This work was supported in part by research grants from Japan Cardiovascular Research Foundation and Japanese Education of Science and Welfare (Nos. 08877110 and 09470164).


   References
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 References
 

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