Antibody therapy against the type-III toxin secretion system on lung infection and sepsis associated with Pseudomonas aeruuginosa

针对铜绿假单胞菌相关肺部感染和脓毒症的 III 型毒素分泌系统抗体治疗

• 批准号: 13671604
• 负责人: SHIME Nobuaki
• 金额: $ 2.56万
• 依托单位: Kyoto Prefectural University of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671604/
• 关键词: Pseudomonas aeruginosa; Pneumonia; Sepsis; Type-III secresion; Neutralizing antibody; Therapy; 治療; 特異的抗体; ショック

Pseudomonas aeruginosa lung infections are frequently associated with high mortality rates, particularly in patients receiving intensive care. Depending on the type III secretion phenotype, P. aeruginosa causes acute organ damage and septic physiology in P. aeruginosa lung infections. In this study, the effects of rabbit-derived polyclonal antibody against PcrV, a protein involved in the translocation of type III secreted toxins of Pseudomonas aeruginosa, was investigated in two animal models of P. aeruginosa sepsis. In a mouse survival study, the intravenous administration of anti-PcrV IgG after the airspace instillation of a lethal dose of P. aeruginosa resulted in the complete survival of the animals. In a rabbit model of septic shock associated with P. aeruginosa-induced lung injury, animals treated with anti-PcrV IgG intracheally or intravenously had significant decreases in lung injury, bacteremia, plasma TNF-α, and significant improvement in the hemodynamic parameters associated with shock compared to animals treated in a similar manner with non-specific control IgG. The administration of anti-PcrV F(ab')_2 showed protective effects comparable to whole anti-PcrV IgG. These results document that the therapeutic administration of anti-PcrV IgG blocks the type III secretion system-mediated virulence of P. aeruginosa and prevents septic shock and death, and that these protective effects are largely Fc-independent. We conclude that antibody therapy neutralizing the type III secretion system has significant potential against lethal P. aeruginosa infections

铜绿假单胞菌肺部感染通常与高死亡率相关，特别是在接受重症监护的患者中。根据III型分泌表型，铜绿假单胞菌在铜绿假单胞菌肺部感染中引起急性器官损伤和脓毒性生理学。在这项研究中，兔源性抗PcrV的多克隆抗体，蛋白参与的第三型分泌毒素的铜绿假单胞菌的移位，在两种动物模型的铜绿假单胞菌脓毒症的影响进行了研究。在小鼠存活研究中，在空域滴注致死剂量的铜绿假单胞菌后静脉内施用抗PcrV IgG导致动物完全存活。在与铜绿假单胞菌诱导的肺损伤相关的脓毒性休克兔模型中，与以类似方式用非特异性对照IgG治疗的动物相比，用抗PcrV IgG进行肠内或静脉内治疗的动物在肺损伤、菌血症、血浆TNF-α方面显著降低，并且与休克相关的血流动力学参数显著改善。抗-PcrV F（ab '）_2的施用显示与全抗-PcrV IgG相当的保护作用。这些结果证明，抗PcrV IgG的治疗性施用阻断了铜绿假单胞菌的III型分泌系统介导的毒力，并防止了脓毒性休克和死亡，并且这些保护作用在很大程度上是Fc非依赖性的。我们的结论是，中和III型分泌系统的抗体治疗对致命的铜绿假单胞菌感染具有重要的潜力

项目成果

芦田ひろみ, 志馬伸朗他: "小児開心周術期おける生体インピーダンス測定の有用性"液体・代謝管理. 18(1). 47-49 (2002)

Hiromi Ashida、Nobuo Shima 等人：“儿科心脏直视手术期间生物阻抗测量的有用性”流体和代谢管理 18(1) (2002)。

志馬 伸朗, 他: "小児開心周術期における血中乳酸濃度による重症度評価"麻酔. 50(7). 752-757 (2001)

Nobuo Shima 等人：“基于儿科心脏直视手术期间血乳酸浓度的严重程度评估”麻醉 50(7) 752-757 (2001)。

Shime N, Sawa T, Wiener-kronish JP, et al.: "Therapeutic Administration of Anti-PcrV F(ab')_2 in Sepsis Associated with Pseudomonas Aeruginosa"J Immunol. 167(10). 5880-5886 (2001)

Shime N、Sawa T、Wiener-kronish JP 等人：“抗 PcrV F(ab)_2 在与铜绿假单胞菌相关的脓毒症中的治疗施用”J 免疫学杂志。

Shime N, Sawa T, Wiener-Kronish JP, et al.: "Liver damage in Pseudomonas aeruginosa bacteremia is associated with the type-III mediated virulence"Am J Respir Crit Care Med. 167(発表予定). (2003)

Shime N、Sawa T、Wiener-Kronish JP 等人：“铜绿假单胞菌菌血症的肝损伤与 III 型介导的毒力有关”Am J Respir Crit Care Med 167（待出版）。

Shime N, et al.: "Specific antibody therapy to psendomouas PcrVis effective to prevent sepsis/septic shock associated with pseudomouas aeruginosa pneumonia"Am J Resp Crit Cave Med. 163(5). A25 (2001)

Shime N 等人：“针对假单胞菌 PcrVi 的特异性抗体疗法可有效预防与铜绿假单胞菌肺炎相关的败血症/感染性休克”Am J Resp Crit Cave Med。