IL-12 prevents mortality in mice infected with Histoplasma capsulatum through induction of IFN-gamma.
IL-12 prevents mortality in mice infected with Histoplasma capsulatum through induction of IFN-gamma.
复制标题
IL-12 通过诱导 IFN-γ 来防止感染荚膜组织胞浆菌的小鼠死亡。
DOI：
10.4049/jimmunol.155.2.785
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发表时间：
1995
影响因子：
4.4
通讯作者：
R. Seder
中科院分区：
文献类型：
--
作者：
Ping Zhou;M. Sieve;J. Bennett;K. J. Kwon;R. Tewari;R. Gazzinelli;Alan Sher;R. Seder
荚膜组织胞浆菌是一种致病性真菌，在世界各地的离散地理位置发现。该真菌侵入网状内皮器官，如免疫活性宿主的脾和肝，在那里它通常是受控的。然而，在具有免疫缺陷的个体中，组织胞浆菌病是一种严重且潜在致命的疾病。对这种感染的抵抗主要是由于T细胞和巨噬细胞介导的细胞免疫应答。此外，IFN-γ在激活巨噬细胞以杀死生物体中至关重要。在此，我们研究了H.以及IL-12在感染过程中的作用。感染H.结果表明，在感染后，用针对IFN-γ、TNF-α或IL-12的中和性Ab处理的荚膜中的小鼠经历了加速的死亡率，表明这些细胞因子的内源性产生在响应感染中起重要作用。相比之下，在感染开始时用IL-12或IL-4的中和Ab处理的小鼠具有显著降低的死亡率。此外，用IL-12感染和治疗的小鼠在体外用特异性H. capsulatum Ag感染的小鼠与对照组相比。如果同时给予IFN-γ的中和抗体，则IL-12的保护作用可以被废除，这表明IL-12在保护中的作用是由IFN-γ介导的。此外，用IL-12处理的感染小鼠的H.与对照动物相比，感染5天后脾细胞中的荚膜。最后，用IL-12处理的感染动物的脾细胞显示它们对有丝分裂原或H.囊状藻属通过在体外培养物中加入IFN-γ或一氧化氮的抑制剂可以恢复反应。上述观察结果表明，IL-12可能是有用的免疫干预对这种机会致病菌。
Histoplasma capsulatum is a pathogenic fungus found in discrete geographic locations throughout the world. The fungus invades the reticuloendothelial organs such as the spleen and liver of immunocompetent hosts where it is usually controlled. However, in individuals with immune deficiency, histoplasmosis is a severe and potentially fatal disease. Resistance to this infection is due primarily to a cellular immune response mediated by T cells and macrophages. Moreover, IFN-gamma is critical in activating macrophages to kill the organism. Herein we study the regulation of cytokine induction in mice infected with H. capsulatum and the effects of IL-12 in the course of infection. Mice infected with H. capsulatum and treated with neutralizing Abs to IFN-gamma, TNF-alpha, or IL-12 experienced accelerated mortality, indicating that endogenous production of these cytokines plays an important role in response to infection. In contrast, mice treated with IL-12 or a neutralizing Ab to IL-4 at the initiation of infection had substantially diminished mortality. Moreover, mice infected and treated with IL-12 show a two- to threefold increase in the amount of IFN-gamma following in vitro stimulation with specific H. capsulatum Ag compared with the control infected mice. The protective effect of IL-12 could be abrogated if a neutralizing Ab to IFN-gamma was given at the same time, demonstrating that the role of IL-12 in protection was mediated by IFN-gamma. Additionally, infected mice treated with IL-12 had a severalfold decrease in the colony counts of H. capsulatum in spleen cells after 5 days of infection as compared with control animals. Lastly, spleen cells from infected animals treated with IL-12 showed a striking decrease in their proliferative response to mitogen or H. capsulatum Ag. Responses could be restored by adding inhibitors of IFN-gamma or of nitric oxide to the in vitro cultures. The above observations suggest that IL-12 may be useful in immunologic intervention against this opportunistic pathogen.