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

我们已经研究了基于奎宁的调节宿主防御隐球菌病的机制，使用肺部和播散性感染的小鼠模型。我们证明了Th 1-Th 2细胞因子产生的不平衡与感染的致命结果密切相关：即，在感染高毒力的C.在新生儿中，Th 2细胞因子的产生在原发感染部位占主导地位，并且这些小鼠在感染后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化为Th 1-主导条件而挽救了它们。有趣的是，该菌株抑制了巨噬细胞产生IL-12，但没有或相反地增强了巨噬细胞合成IL-10，这可能表明该机制参与了细胞因子平衡向Th 2优势状态的转变。所有这些都对T ...更多信息 淋巴细胞和巨噬细胞的清除在肺中产生不良。明显地，发现由淋巴细胞和巨噬细胞组成的炎性白细胞的积聚非常少。IL- 12处理诱导淋巴细胞和巨噬细胞的显着积累和多核巨细胞在肺中的形成，这是非常一致的生产这些单核白细胞运输chemokines.In我们最近的研究中，我们已经证明了IL-12和IL-18在宿主防御隐球菌感染使用IL-12，IL-18和IL-12/IL-18 KO小鼠的重要作用。在这些小鼠中，与野生型小鼠相比，IFN-γ合成和宿主抗性以及对微生物的DTH反应受损。IL-12 KO小鼠的损伤比IL-18 KO小鼠更严重。在IL 12/IL-18 KO小鼠中，IFN-γ产生几乎完全消除，宿主防御与IFN-γKO小鼠一样严重受损。与这些结果一致，用IL-12或IL-18处理增加了宿主对C.新人类这种活性在前一种细胞因子中比在后者中更大。在体外和体内研究中，这两种IFN-γ诱导细胞因子联合处理可协同诱导IFN-γ的产生，增强宿主对青霉菌的抵抗力。我们发现，裸鼠对马尔尼菲青霉感染高度敏感，过继转移来自正常小鼠的富含T细胞的脾细胞使裸鼠对这种感染具有抵抗力。此外，我们证明了小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，并且人类中性粒细胞的这种活性被各种细胞因子如GM-CSF、G-CSF、IL-8增强。TNF-γ和IFN-γ以及最有效的GM-CSF效应由颗粒酶介导，而不是由氧自由基介导。少

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