Therapy with a combination of low doses of interleukin 12 and chloroquine completely cures blood-stage malaria, prevents severe anemia, and induces immunity to reinfection
Therapy with a combination of low doses of interleukin 12 and chloroquine completely cures blood-stage malaria, prevents severe anemia, and induces immunity to reinfection
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DOI：
10.1128/iai.67.2.513-519.1999
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发表时间：
1999-02-01
影响因子：
3.1
通讯作者：
Stevenson, MM
中科院分区：
文献类型：
--
作者：
Mohan, K;Sam, H;Stevenson, MM
免疫调节细胞因子白细胞介素12（IL-12）诱导宿主对实验性疟疾的抗性。在这项研究中，我们测试了使用IL-12与氯喹（CQ）组合来拯救易感A/J小鼠免于致死血液期夏氏疟原虫AS感染的可行性。低剂量CQ和IL-12的联合治疗导致寄生虫负荷减少>15倍，并且具有已建立感染的A/J小鼠的存活率为100%。与死于严重贫血的对照小鼠相比，CQ加IL-12治疗的小鼠在骨髓和脾脏中具有显著更高的早期和晚期红系祖细胞，导致显著更高的血细胞比容、红细胞计数和网织红细胞百分比。这些小鼠脾细胞产生的寄生虫特异性γ干扰素（IFN-γ）相对于对照上调>20倍，同时IFN-γ mRNA表达增强。此外，从脾细胞中IL-12受体β 1和β 2亚基的mRNA表达增加可以看出，CQ加IL-12处理的小鼠中对IL-12的反应性增强，下游IFN-γ产生增加。此外，这种联合治疗诱导更高水平的抗疟疾抗体比CQ单独以及对再感染的无菌免疫。由于IL-12可以以低剂量使用，并且即使在已建立的感染中也是有效的，因此在人类疟疾中使用这种免疫化疗方法可能是可行的。
The immunoregulatory cytokine interleukin 12 (IL-12) induces host resistance against experimental malaria. In this study, we tested the feasibility of using IL-12 in combination with chloroquine (CQ) to rescue susceptible A/J mice from lethal blood-stage Plasmodium chabaudi AS infection. Combined treatment with low doses of CQ and IL-12 resulted in a >15-fold reduction in the parasite load and 100% survival of A/J mice with established infections. Compared to control mice, which succumbed to severe anemia, CQ-plus-IL-12-treated mice had significantly higher early- and late-stage erythroid-cell progenitors in the bone marrow and spleen, resulting in significantly higher hematocrits, erythrocyte counts, and percentages of reticulocytes. Production of parasite-specific gamma interferon (IFN-gamma) by splenocytes from these mice was upregulated >20-fold relative to controls in parallel with enhanced IFN-gamma mRNA expression. Further, enhanced responsiveness to IL-12 and increased downstream IFN-gamma production in CQ-plus-IL-12-treated mice was evident from increased mRNA expression for the beta 1 and beta 2 subunits of IL-12 receptor in the splenocytes. Moreover, this combined therapy induced higher levels of anti-malaria antibodies than did CQ alone as well as sterile immunity against reinfection. Because IL-12 can be used at low doses and is effective even in established infections, it may be feasible to use this immunochemotherapeutic approach in human malaria.