Romani L, Mencacci A, Tonnetti L, Spaccapelo R, Cenci E, Puccetti P, Wolf S F, Bistoni F
Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Italy.
J Immunol. 1994 Dec 1;153(11):5167-75.
In murine models of systemic candidiasis, healing and nonhealing patterns of disease are associated with preferential expansion of Th1 and Th2 cells, respectively. As previous studies have shown IL-12 to be expressed transcriptionally in healer mice and to be required for Th1 development in vitro, this cytokine might play a role in Candida-driven Th1 cell differentiation in vivo. In the present study, IL-12-neutralizing Abs or recombinant IL-12 were administered to mice with healing or progressive candidiasis, respectively, and the animals were monitored for mortality, resistance to reinfection, serum levels of specific Abs, and IFN-gamma, IL-4, and IL-10 message/protein expression by CD4+ cells. In self-limiting infection by a yeast vaccine strain, neutralization of IL-12 ablated development of acquired anticandidal resistance and led to appearance of Candida-specific IgE and IL-4-producing cells. In mice with progressive systemic disease as well as in a mucosal infection model, administration of IL-12 did not result in therapeutic activity under conditions of yeast infection that would instead be resolved by serologic ablation of IL-4 or IL-10. Yet, in systemically infected mice cured by anti-IL-4 or anti-IL-10 therapy, the emergence of a Th1 response correlated with the detection of high levels of circulating IL-12 and splenic IL-12 transcripts. Although exogenous IL-12 may not be sufficient for Th conversion in the presence of an overwhelming IL-4/IL-10 response, endogenous production of IL-12 may be both required and prognostic for Th1 differentiation in vivo.
在系统性念珠菌病的小鼠模型中，疾病的愈合和不愈合模式分别与Th1细胞和Th2细胞的优先扩增相关。正如先前研究表明，IL-12在愈合小鼠中转录表达，并且在体外是Th1发育所必需的，这种细胞因子可能在体内念珠菌驱动的Th1细胞分化中发挥作用。在本研究中，分别向患有愈合性或进行性念珠菌病的小鼠施用IL-12中和抗体或重组IL-12，并监测动物的死亡率、对再感染的抵抗力、特异性抗体的血清水平以及CD4 +细胞的IFN-γ、IL-4和IL-10信使/蛋白表达。在酵母疫苗株的自限性感染中，IL-12的中和消除了获得性抗念珠菌抗性的发展，并导致念珠菌特异性IgE和产生IL-4的细胞出现。在患有进行性全身性疾病的小鼠以及粘膜感染模型中，在酵母感染的情况下，施用IL-12并未产生治疗活性，而通过血清学消除IL-4或IL-10反而可以解决。然而，在通过抗IL-4或抗IL-10疗法治愈的全身感染小鼠中，Th1反应的出现与检测到高水平的循环IL-12和脾脏IL-12转录本相关。尽管在存在压倒性的IL-4 / IL-10反应时，外源性IL-12可能不足以实现Th转化，但内源性IL-12的产生可能是体内Th1分化所必需的且具有预后意义。
