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

本研究通过阻断单核细胞增生李斯特菌（Listeria monocytogenes）和金黄色葡萄球菌（Staphylococcus aureus，MRSA）致死性感染诱导的细胞因子级联反应来预防和治疗严重细菌性感染性疾病.结果1.感染小鼠在死亡前的血液和器官中检测到高滴度的内源性γ干扰素（IFN-γ）、肿瘤坏死因子（TNF）和白细胞介素-6（IL-6）.将IFN-γ、TNF或IL-6的单克隆抗体（mAb）给予单核细胞增生李斯特菌感染的小鼠不影响致死性感染，而抗IFN-γ mAb保护MRSA感染的小鼠免于致死性感染。在感染前或感染后给予mAb均观察到保护作用。抗IFN-γ mAb对大肠杆菌脂多糖诱导的休克小鼠也有保护作用.糖皮质激素、地塞米松对单核细胞增生李斯特菌致死性感染小鼠的细胞因子级联反应有抑制作用.用抗CD 3单克隆抗体刺激T淋巴细胞，诱导细胞因子级联反应，对单核细胞增生李斯特菌致死性感染的小鼠产生保护作用，提示阻断或调节细胞因子级联反应可能是治疗重症细菌感染性疾病的有效方法。特别强调了特异性阻断内源性IFN-γ可能是治疗严重MRSA感染的有效手段。

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.