IL-12-induced protection against blood-stage Plasmodium chabaudi AS requires IFN-gamma and TNF-alpha and occurs via a nitric oxide-dependent mechanism.
IL-12-induced protection against blood-stage Plasmodium chabaudi AS requires IFN-gamma and TNF-alpha and occurs via a nitric oxide-dependent mechanism.
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DOI：
10.4049/jimmunol.155.5.2545
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发表时间：
1995-09
影响因子：
4.4
通讯作者：
M. Stevenson;M. Tam;S. Wolf;A. Sher
中科院分区：
文献类型：
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作者：
M. Stevenson;M. Tam;S. Wolf;A. Sher
分析IL-12对血液期沙包虫AS保护性免疫的影响。在感染当天和感染后5天，用不同剂量的rIL-12(0.025-0.3微克)治疗易感A/J小鼠，可显著降低最高寄生虫血症水平，但仅0.1微克治疗可提高存活率。用相同方案用0.1微克rIL-12治疗耐药B6小鼠，也显著降低了峰值寄生虫血症水平，但40%的动物死亡。用抗IL-12单抗治疗这些小鼠会导致更严重的感染过程，但存活率没有明显改变。对感染过程中IL-12诱导A/J小鼠产生耐药性的机制进行了研究。与未经处理的小鼠的脾细胞相比，IL-12处理的小鼠在感染后第7天自发产生的干扰素-γ水平显著高于未处理的小鼠，以及对ConA或Ag刺激的反应。经IL-12处理的小鼠血清中的干扰素-γ和肿瘤坏死因子-α水平显著升高，这与一氧化氮(NO)代谢物NO3-的高水平有关。此外，研究发现，去除CD4+T细胞可以消除IL-12诱导的抵抗力。给IL-12处理的小鼠注射中和抗干扰素-γ或肿瘤坏死因子-α的单抗，两种细胞因子同时耗尽可导致100%的死亡。给IL-12处理的小鼠注射细胞因子诱导型一氧化氮合酶的选择性抑制剂氨基胍，以研究NO的作用。每天服用2次9 mg氨基胍可显著提高死亡率，但对寄生虫血症无明显影响。综上所述，这些结果表明，IL-12通过涉及细胞因子干扰素-γ和肿瘤坏死因子-α的CD4+Th1反应调节对沙鲍迪肺炎耐药的形成，并且部分不依赖。因此，给予适当剂量的IL-12可能有助于诱导对血态疟疾的保护性免疫。
The effects of IL-12 administration on the development of protective immunity to blood-stage Plasmodium chabaudi AS were analyzed. Treatment of susceptible A/J mice on the day of infection and for 5 days postinfection with various doses 0.025-0.3 microgram) of rIL-12 significantly decreased the peak parasitemia level, but only treatment with 0.1 microgram resulted in increased survival. Treatment of resistant B6 mice with 0.1 microgram of rIL-12 using the same regimen also significantly decreased the peak parasitemia level, but 40% of the animals died. Treatment of these mice with anti-IL-12 mAb resulted in a more severe course of infection, but survival was not significantly altered. The mechanism of IL-12-induced resistance was examined in A/J mice during infection. Compared with spleen cells from untreated mice, cells from IL-12-treated mice produced significantly higher levels of IFN-gamma spontaneously as well as in response to Con A or Ag stimulation on day 7 postinfection. Significantly higher levels of INF-gamma and TNF-alpha were found in the sera of IL-12-treated mice, which correlated with high levels of the nitric oxide (NO) metabolite, NO3-. Furthermore, CD4+T cell depletion was found to abrogate IL-12-induced resistance. Administration of neutralizing mAb against IFN-gamma or TNF-alpha to IL-12-treated mice showed that simultaneous depletion of both cytokines resulted in 100% mortality. The role of NO was investigated by administration of aminoguanidine, a selective inhibitor of cytokine-inducible nitric oxide synthase, to IL-12-treated mice. Significantly increased mortality was observed following treatment twice daily with 9 mg of aminoguanidine, but there was no effect on parasitemia. In conclusion, these results demonstrate that IL-12 regulates the development of resistance to P. chabaudi AS via a CD4+ Th1 response, which involves the cytokines IFN-gamma and TNF-alpha, and is in part NO dependent. Therefore, IL-12, given in the appropriate dose, may be useful in the induction of protective immunity to blood-state malaria.