Lavigne L M, Schopf L R, Chung C L, Maylor R, Sypek J P
Department of Preclinical Research and Development, Genetics Institute, Inc., Andover, MA 01810, USA.
J Immunol. 1998 Jan 1;160(1):284-92.
Studies on murine candidiasis suggest that resistance to disease is linked to a Th1 response and production of IFN-gamma, while failure to elicit protection is associated with a Th2 response and production of IL-4 and IL-10. Experimental infection of C57BL/6 mice, IL-12 treatment of these mice, or both infection and IL-12 treatment resulted in a characteristic Th1 cytokine mRNA profile as measured by quantitative competitive PCR. Specifically, little or no IL-4 transcripts were detected, while IFN-gamma message was elevated, particularly with IL-12 treatment. Despite its role in driving increased IFN-gamma expression and production, IL-12 treatment, paradoxically, promoted disease progression in our model. Therefore, we examined the effect of IFN-gamma neutralization on IL-12-induced susceptibility to infection. None of the systemically infected mice receiving IL-12 alone survived, while IL-12- and anti-IFN-gamma-treated mice had a 70% survival rate, similar to that after infection alone. These results suggested that IFN-gamma induced by IL-12 treatment contributed to lethality. However, in separate studies, IFN-gamma knockout mice were more susceptible to infection than their wild-type counterparts, suggesting that IFN-gamma is required for resistance. Nonetheless, infected IFN-gamma knockout mice treated with recombinant murine IL-12 exhibited enhanced resistance, suggesting that the toxicities observed with IL-12 are directly attributable to IFN-gamma and that an optimal immune response to Candida infections necessitates a finely tuned balance of IFN-gamma production. Thus, we propose that although IFN-gamma can drive resistance, the overproduction of IFN-gamma during candidiasis, mediated by IL-12 administration, leads to enhanced susceptibility.
对小鼠念珠菌病的研究表明，对该病的抵抗力与Th1反应及IFN-γ的产生有关，而未能引发保护作用则与Th2反应及IL-4和IL-10的产生有关。对C57BL/6小鼠进行实验性感染、用IL-12处理这些小鼠或同时进行感染和IL-12处理，通过定量竞争PCR检测，均产生了特征性的Th1细胞因子mRNA谱。具体而言，检测到很少或没有IL-4转录本，而IFN-γ的信息增加，特别是在用IL-12处理时。尽管IL-12在驱动IFN-γ表达和产生增加方面发挥作用，但矛盾的是，在我们的模型中，IL-12处理促进了疾病进展。因此，我们研究了IFN-γ中和对IL-12诱导的感染易感性的影响。单独接受IL-12的全身感染小鼠无一存活，而接受IL-12和抗IFN-γ处理的小鼠存活率为70%，与单独感染后的存活率相似。这些结果表明，IL-12处理诱导的IFN-γ导致了致死率。然而，在单独的研究中，IFN-γ基因敲除小鼠比其野生型对应物更容易感染，这表明IFN-γ是抵抗所必需的。尽管如此，用重组鼠IL-12处理的感染IFN-γ基因敲除小鼠表现出增强的抵抗力，这表明观察到的IL-12毒性直接归因于IFN-γ，并且对念珠菌感染的最佳免疫反应需要IFN-γ产生的精细平衡。因此，我们提出，尽管IFN-γ可以驱动抵抗力，但在念珠菌病期间由IL-12给药介导的IFN-γ过量产生会导致易感性增强。
