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

通过阻断细胞因子级联开发治疗严重细菌感染性疾病的方法

• 批准号: 03557021
• 负责人: NAKANE Akio
• 金额: $ 6.78万
• 依托单位: Hokkaido University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Developmental Scientific Research (B)
• 财政年份: 1991
• 资助国家: 日本
• 起止时间: 1991 至 1993
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-03557021/
• 关键词: MRSA; Listeria monocytogenes; Staphylococcus aureus; Cytokine; IFN-gamma; TNF; IL-6; Bacterial infectious diseases; LPS; 致死感染; 予防; 治療; 抗ヒトTNFmAb; 抗マウスTNFmAb; 抗マウスIFN-γmAb; 抗CD3mAb; デキサメタゾン; Tリンパ球サブセット

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.

我们在小鼠模型中研究了通过阻断由单核细胞增多性李斯特菌和金黄色葡萄球菌（MRSA）致命感染引起的细胞因子级联来预防和治疗严重细菌感染性疾病的进展。1．感染小鼠临死前血流和脏器中检测到高滴度的内源性γ干扰素(IFN-gamma)、肿瘤坏死因子(TNF)和白细胞介素6(IL-6)。 2．将针对 IFN-γ、TNF 或 IL-6 的单克隆抗体 (mAb) 给予单核细胞增多性李斯特菌感染的小鼠不会影响致死性感染，而抗 IFN-γ mAb 可以保护 MRSA 感染的小鼠免受致死性感染。在感染之前或之后施用单克隆抗体时，观察到了保护作用。抗IFN-γ单克隆抗体对大肠杆菌脂多糖休克小鼠也有保护作用。 3．当糖皮质激素、地塞米松治疗抑制细胞因子级联反应时，在受到单核细胞增多性李斯特氏菌致死性感染的小鼠中证实了这种保护作用。 4．当用 CD3 分子的 mAb 刺激 T 淋巴细胞诱导细胞因子级联时，在受到单核细胞增多性李斯特菌致死性感染的小鼠中证明了保护作用。这些结果表明通过阻断或调节细胞因子级联可以治疗严重的细菌感染性疾病。特别强调的是，特异性阻断内源性IFN-γ可能是治疗严重MRSA感染患者的有效手段。

项目成果

Toshikazu Shirahata: "Enhancement by recombinant human interleukin 2 of host resistance to Toxoplasma gondii infection in pregnant mice" Microbiol.Immunol.37(7). 585-590 (1993)

Toshikazu Shirahata：“通过重组人白细胞介素 2 增强怀孕小鼠对弓形虫感染的宿主抵抗力”Microbiol.Immunol.37(7)。

Akio Nakane: "Prophylactic effect of dexamethasone against a lethal infection with Listeria monocytogenes in mice which show overproduction of endogenous cytokines"

Akio Nakane：“地塞米松对小鼠单核细胞增多性李斯特菌致命感染的预防作用，该感染表现出内源性细胞因子的过度产生”

Toshikazu Shirahata: "Enhancement by recombinant human interleukin 2 of host resistance to Toxoplasma gondii infection in pregnant mice" Microbiology and Immunology. 37. 585-590 (1993)

Toshikazu Shirahata：“通过重组人白细胞介素 2 增强怀孕小鼠对弓形虫感染的宿主抵抗力”微生物学和免疫学。

Fumio Kaneko: "Role of cell-mediated immune reaction in blister formation of bullos pemphigoid" Clinical and Laboratory Investigations. 184. 34-39 (1992)

Fumio Kaneko：“细胞介导的免疫反应在大疱性类天疱疮形成水疱中的作用”临床和实验室研究。

Akio Nakane: "Endogenous gamma interferon-independent host resistance against Listeria monocytogenes infection in CD4+T cell-and asialo GM1+cell-depleted mice" Infection and Immunity. 59. 3439-3445 (1991)

Akio Nakane：“在 CD4 T 细胞和 asialo GM1 细胞耗尽的小鼠中，内源性 γ 干扰素独立的宿主对单核细胞增生李斯特菌感染的抵抗力”感染和免疫。