Study on the pathogenic mechanism of opportunistic fungal infectious diseases in AIDS patients

艾滋病患者机会性真菌感染性疾病发病机制研究

• 批准号: 09670292
• 负责人: KAWAKAMI Kazuyoshi
• 金额: $ 1.6万
• 依托单位: University of the Ryukyus
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670292/
• 关键词: Opportunistic fungal diseases; Cryptococcus neoformans; Penicillium marneffei; AIDS; Th1-Th2 blalance; IL-12; Il-18; chemokines; Cryptococcus neoformans; Penicillium marneffei; Il-18; IFN-gamma; 可溶性CD4; 好中球; Candida albicans; 一酸化窒素; 活性酸素 /

We have studied on the mechanism of cytokine-based regulation for host defense against cryptococcosis using a murine model of pulmonary and disseminated infection. We demonstrated that imbalance of Th1-Th2 cytokine production was well associated with the fatal outcome of infection: that is, in infection with a highly virulent strain of C. neoformans, Th2 cytokine production was dominant over Th1 in the primary infection site and these mice all died with 6 weeks post-infection, while IL-12 treatment saved them by converting the imbalanced cytokine synthesis to Th1-dominant condition. Interestingly, this strain suppressed the IL-12 production but did not or rather enhanced the synthesis of IL-10 by macrophages, which may suggest the involvement of this mechanism in the shifted cytokine balance toward Th2 predominant condition.Furthermore, in the fatal infection model, CC chemokines, such as MCP-1, RANTES, MIP-1α and MIP-1β, and IP-10, a CXC chemokine, all of which are important for the t … More rafficking of lymphocytes and macrophages were poorly produced in lungs. Compatibly, the accumulation of inflammatory leukocytes composing of lymphocytes and macrophages was found very poor. IL- 12 treatment induced the marked accumulation of lymphocytes and macrophages and formation of multinuclear giant cells in the lungs, which was well consistent with the production of these mononuclear leukocyte-trafficking chemokines.In our recent study, we have demonstrated the essential role for IL-12 and IL-18 in host defense against cryptococcal infection using IL-12, IL-18 and IL-12/IL-18KO mice. In these mice, IFN-γ synthesis and host resistance and DTH response to the microorganism were impaired compared to those in wild-type mice. The impairment was more profound in IL-12KO mice than in IL-18KO mice. In IL12/IL-18KO mice, IFN-γ production was almost completely abrogated and host defense was as profoundly impaired as in IFN-γKO mice. Compatibly with these results, treatment with either IL-12 or IL-18 increased the host protection against fatal infection with C. neoformans. Such activity was greater in the former cytokine than in the latter. Combined treatment with these two IFN-γ-inducing cytokines synergistically induced the production of IFN-γ and potentiated the host resistance to this pathogen both in in vitro and in vivo studies.In our other studies, we firstly demonstrated that host defense to Penicillium infection was mediated by cellular immunity. We showed that nude mice were highly susceptible to the infection with P. marneffei and that adoptive transfer of T cell-enriched spleen cells from normal mice rendered nude mice resistant to this infection. Furthermore, we demonstrated that fungicidal activity of murine macrophages was mediated by nitric oxide, not by superoxide anion and that such activity of human neutrophils was potentiated by various cytokines, such as GM-CSF, G-CSF, IL-8. TNF-γ and IFN-γ and the GM-CSF effect, which was most potent, was mediated by granular enzymes, not by oxygen radicals. Less

我们使用肺部和播散性感染的小鼠模型研究了基于细胞因子的调节宿主防御隐球菌病的机制。我们证明，Th1-Th2细胞因子产生的不平衡与感染的致命结果密切相关：也就是说，在感染新型隐球菌的高毒力菌株时，在原发感染部位，Th2细胞因子的产生比Th1占主导地位，这些小鼠在感染后6周全部死亡，而IL-12治疗通过将不平衡的细胞因子合成转变为Th1占主导地位而挽救了它们。有趣的是，该菌株抑制了IL-12的产生，但没有或相反增强了巨噬细胞对IL-10的合成，这可能表明该机制参与了细胞因子平衡向Th2占主导地位的转变。此外，在致命感染模型中，CC趋化因子，如MCP-1、RANTES、MIP-1α和MIP-1β，以及IP-10（一种CXC趋化因子），都 其中对于肺部的淋巴细胞和巨噬细胞的增殖很重要。相容地，发现由淋巴细胞和巨噬细胞组成的炎性白细胞的积累非常差。 IL-12 治疗诱导肺部淋巴细胞和巨噬细胞的显着积累以及多核巨细胞的形成，这与这些单核白细胞运输趋化因子的产生非常一致。在我们最近的研究中，我们使用 IL-12、IL-18 和 IL-12 证明了 IL-12 和 IL-18 在宿主防御隐球菌感染中的重要作用。 IL-12/IL-18KO 小鼠。与野生型小鼠相比，这些小鼠的 IFN-γ 合成以及宿主对微生物的抵抗力和 DTH 反应均受损。 IL-12KO 小鼠的损伤比 IL-18KO 小鼠更严重。在 IL12/IL-18KO 小鼠中，IFN-γ 的产生几乎完全消除，宿主防御与 IFN-γKO 小鼠一样严重受损。与这些结果相一致的是，IL-12 或 IL-18 治疗增强了宿主对新型隐球菌致命感染的保护作用。前一种细胞因子的这种活性比后者更大。在体外和体内研究中，这两种诱导IFN-γ的细胞因子联合治疗可协同诱导IFN-γ的产生，并增强宿主对该病原体的抵抗力。在我们的其他研究中，我们首先证明宿主对青霉菌感染的防御是由细胞免疫介导的。我们发现，裸鼠对马尔尼菲疟原虫的感染高度敏感，并且从正常小鼠中过继转移富含T细胞的脾细胞使裸鼠能够抵抗这种感染。此外，我们证明鼠巨噬细胞的杀真菌活性是由一氧化氮介导的，而不是由超氧阴离子介导的，并且人中性粒细胞的这种活性被多种细胞因子（例如GM-CSF、G-CSF、IL-8）增强。 TNF-γ 和 IFN-γ 以及最有效的 GM-CSF 作用是由颗粒酶介导的，而不是由氧自由基介导。较少的

项目成果

Zhang, T. et al.: "Interleukin (IL)-12 and IL-18 synergistically induce the fungicidal activity murine peritonal exudate cells against Cryptococcus neofornans through production of interferon-γ by natural killer cells"Infection and Immunity. 65. 3594-3599

张，T. 等人：“白细胞介素 (IL)-12 和 IL-18 通过自然杀伤细胞产生干扰素-γ，协同诱导小鼠腹膜渗出细胞对新生隐球菌的杀真菌活性”感染和免疫 65。 3599

Qureshi, M.H. et al.: "Combined effect of IL-12 and IL-18 on the clinical course and local cytokine production in murine pulmonary infection with Cryptococcus neoformans"European Journal of Immunology. vol.29. 491-497 (1999)

库雷希，M.H.

Kawakami, K et al.: "Role of TNF-αin the induction of fungicidal activity of mouse peritoneal exudat cells against Cryptococcus neoformans by IL-12 and IL-18"Cellular Immunology. 193. 9-16 (1999)

Kawakami，K 等人：“TNF-α 在通过 IL-12 和 IL-18 诱导小鼠腹膜渗出物细胞针对新生隐球菌的杀真菌活性中的作用”细胞免疫学 193. 9-16 (1999)。

Kawakami, K et al.: "Chemokine responses and accumulation of inflammatory cells in the lungs of mice infected with highly virulent Cyptococcus neoformans: effects of interleukin-12 FEMS Immunology and Medical Microbiology"FEMS Immunology and Medical Micro

Kawakami, K 等人：“感染高毒力新生隐球菌的小鼠肺部炎症细胞的趋化反应和积聚：白细胞介素 12 FEMS 免疫学和医学微生物学的影响”FEMS 免疫学和医学微生物学

Kawakami, K: "Recent research Development in Antimicrobial Agents and chemotherapy"Research Signpost. 281-295 (1999)

Kawakami, K：“抗菌剂和化疗的最新研究进展”研究路标。