Development of the therapy of severe bacterial infectious dieases by blockade of cytokine cascade

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We investigated development of the prophylaxis and therapy of severe bacterial infectious diseases by blockade of the cytokine cascade which is induced by the lethal infections with Listeria monocytogenes and Staphylococcus aureus (MRSA) in the mouse models.1. The high titers of endogenous gamma interferon (IFN-gamma), tumor necrosis factor (TNF) and interleukin-6 (IL-6) were detected in the bloodstreams and organs of the infected mice just before death.2. The administration of monoclonal antibodies (mAbs) to IFN-gamma, TNF or IL-6 into L.monocytogenes-infected mice did not affect the lethal infection, whereas anti-IFN-gamma mAb protected MRSA-infected mice from the lethal infection. The protective effect was observed when the mAb was administered either before or after infection. The Protective effect of anti-IFN-gamma mAb was also showed in mice which were suffered from Escherichia coli-derived lipopolysaccharide-induced shock.3. The protective effect was demonstrated in mice which received a lethal infection with L.monocytogenes when the cytokine cascade was suppressed by the treatment of glucocorticoid, dexamethasone.4. The protective effect was demonstrated in mice which received a lethal infection with L.monocytogenes when the cytokine cascade was induced by stimulation of T lymphocytes with the mAb to CD3 molecule.These results demonstrate the possible therapy for severe bacterial infectious diseases by blockade or modulation of cytokine cascade. Especially, it is emphasized that the specific blockade of endogenous IFN-gamma may be an available mean to treat the patients who suffered from the severe MRSA infection.