Louie A, Baltch A L, Smith R P, Franke M A, Ritz W J, Singh J K, Gordon M A
Infectious Diseases Section, Stratton Veterans Affairs Medical Center, Albany, New York.
Infect Immun. 1994 Jul;62(7):2761-72. doi: 10.1128/iai.62.7.2761-2772.1994.
The role of tumor necrosis factor alpha (TNF-alpha) in host defense against systemic Candida albicans infection was evaluated in a murine model of systemic candidiasis in which uniform death occurred between 5 and 6 days after infection. TNF-alpha was first detected at 16 h postinfection and progressively increased thereafter. Peak levels (700 to 900 pg/ml) were measured in mice near death. Administration of 0.5 to 1.0 mg of polyclonal immunoglobulin G (IgG) TNF-alpha antibody (TNF-alpha Ab) to mice 2 h preinfection neutralized serum TNF-alpha for up to 30 h. However, this regimen shortened survival from a mean of 5.5 days for IgG controls to 3.4 days (P = 1.9 x 10(-12)). Semiquantitative cultures of spleen, lung, liver, and kidney conducted at 1, 2, and 3 days postinfection found colony counts of spleen and kidney to be significantly higher for TNF-alpha Ab recipients but only for the first 48 h. Administration of 1.5 and 1.0 mg of TNF-alpha Ab at 2 h before and 48 h after fungal injection, respectively, shortened the mean survival from 4.9 to 2.3 days (P = 5.2 x 10(-8)). This regimen neutralized serum TNF-alpha throughout infection. With this regimen, colony counts of all organs were significantly higher in TNF-alpha Ab recipients at 1, 2, and 3 days postinfection. Histopathologic studies showed an increase in the number and size of C. albicans foci in tissues. Peripheral leukocyte counts and inflammatory response in tissue were similar for TNF-alpha Ab and IgG sham recipients. In vitro, incubation of C. albicans with four to eight times the peak serum levels of TNF-alpha for up to 24 h did not inhibit the rate of germ tube or pseudohypha formation. Thus, TNF-alpha that was produced during infection with C. albicans augmented host resistance against this organism and prolonged survival. The protective effect of TNF-alpha was not mediated by increased leukocytes in blood or tissues nor by a direct anticandidal effect of TNF-alpha. This study suggests that the administration of exogenous TNF-alpha may enhance host resistance against systemic C. albicans infection and may improve host survival.
在系统性念珠菌病的小鼠模型中评估了肿瘤坏死因子α（TNF-α）在宿主抵御白色念珠菌全身性感染中的作用，该模型中感染后5至6天内小鼠会全部死亡。TNF-α在感染后16小时首次被检测到，此后逐渐增加。在濒死小鼠中测得峰值水平（700至900 pg/ml）。在感染前2小时给小鼠注射0.5至1.0 mg多克隆免疫球蛋白G（IgG）TNF-α抗体（TNF-α Ab）可中和血清TNF-α长达30小时。然而，这种方案将生存期从IgG对照组的平均5.5天缩短至3.4天（P = 1.9×10⁻¹²）。在感染后1、2和3天对脾脏、肺、肝脏和肾脏进行的半定量培养发现，TNF-α Ab接受者的脾脏和肾脏菌落计数显著更高，但仅在最初48小时内如此。分别在真菌注射前2小时和注射后48小时给予1.5和1.0 mg TNF-α Ab，将平均生存期从4.9天缩短至2.3天（P = 5.2×10⁻⁸）。这种方案在整个感染过程中中和血清TNF-α。采用这种方案时，在感染后1、2和3天，TNF-α Ab接受者所有器官的菌落计数均显著更高。组织病理学研究显示组织中白色念珠菌病灶的数量和大小增加。TNF-α Ab接受者和IgG假注射接受者的外周白细胞计数和组织中的炎症反应相似。在体外，将白色念珠菌与高达血清TNF-α峰值水平4至8倍的物质一起孵育长达24小时，并未抑制芽管或假菌丝形成的速率。因此，白色念珠菌感染期间产生的TNF-α增强了宿主对该病原体的抵抗力并延长了生存期。TNF-α的保护作用不是由血液或组织中白细胞增多介导的，也不是由TNF-α的直接抗念珠菌作用介导的。这项研究表明，给予外源性TNF-α可能增强宿主对全身性白色念珠菌感染的抵抗力并可能改善宿主生存期。
