Effects of immunoglobulin upon murine myocarditis caused by influenza A virus: superiority of intact type to F(ab')2 type

Abstract

Influenza viruses play the largest role in the worldwide epidemiology of infectious diseases. Management of some inflammatory disease (eg, Kawasaki disease) with immunoglobulin has been demonstrated to be effective. We examined the effects of intact type and F(ab')2 type of immunoglobulin preparations upon murine influenza A virus myocarditis in mice. In vitro study showed that intact type and F(ab')2 type of immunoglobulin preparations exhibit antiviral activities against many substrains of influenza virus and other cardiotropic viruses. Dose-dependent suppression of an influenza A virus (NWS) was demonstrated by management with both intact immunoglobulin and F(ab')2 fragments of immunoglobulin. The dose inhibiting 50% of plaques was the same between intact type and F(ab')2 type (both 0.0002 mg/dl). Intact immunoglobulin, but not F(ab')2 fragments of immunoglobulin, suppressed serum macrophage inflammatory protein-2 (MIP-2) productions in influenza A virus-infected macrophages in vitro, which is a murine counterpart of interleukin-8. This suppression of MIP-2 production by intact immunoglobulin treatment was blocked by a specific Fc receptor (Fc gamma III/II receptor) antibody pretreatment. Intact immunoglobulin or F(ab')2 fragments of immunoglobulin were administered to virus-inoculated A/J mice intraperitoneally daily, starting simultaneously with virus inoculation (Experiment I) and 2 days after the virus inoculation (Experiment II), until 10 days after virus inoculation. In Experiment I, survival was higher in treated than in control mice; intact type and F(ab')2 type immunoglobulins administration completely suppressed the development of myocarditis. In Experiment II, survival rate was significantly higher and myocarditis was less severe in intact immunoglobulin-treated mice, but not in F(ab')2 fragments-treated mice compared with untreated mice. Serum neutralizing antibody titers in treated mice were significantly higher compared with untreated mice in Experiments I and II. In addition, serum MIP-2 concentrations in intact immunoglobulin-treated mice, but not in F(ab')2 fragments-treated mice, were lower compared with untreated mice in Experiment II. Immunoglobulin therapy suppresses influenza A virus myocarditis by increasing neutralizing antibody titers and the suppression of myocardial virus activities. From the standpoint of suppression of MIP-2 concentrations, intact type is superior to F(ab')2 type. Thus, immunoglobulin treatment may be promising for prevention of influenza virus myocarditis.