Endogenous interleukin 12 (IL-12) regulates granuloma formation induced by eggs of Schistosoma mansoni and exogenous IL-12 both inhibits and prophylactically immunizes against egg pathology.
Endogenous interleukin 12 (IL-12) regulates granuloma formation induced by eggs of Schistosoma mansoni and exogenous IL-12 both inhibits and prophylactically immunizes against egg pathology.
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DOI：
10.1084/jem.179.5.1551
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发表时间：
1994-05-01
期刊：
影响因子：
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通讯作者：
Sher A
中科院分区：
文献类型：
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作者：
Wynn TA;Eltoum I;Oswald IP;Cheever AW;Sher A
感染曼氏血吸虫的人的死亡主要是由于寄生虫卵沉积在汇管区，在汇管区它们诱导肉芽肿反应。在感染这种蠕虫的小鼠中，肉芽肿形成是一种CD 4 + T辅助（Th）细胞依赖性过程，与强烈的Th 2细胞因子反应相关，该反应似乎通过Th 0期演变。在这份报告中，我们问是否内源性合成或外源性诱导的干扰素（IFN）γ通过其抑制Th 2细胞扩增发挥调节作用的鸡蛋病理。IFN-γ或自然杀伤细胞的耗竭导致静脉注射鸡蛋周围肉芽肿形成的显著增强，并与Th 2增加和Th 1和白细胞介素（IL）12 mRNA表达减少相关。当用IL-12特异性的中和单克隆抗体处理卵注射小鼠时，发生了类似的变化，表明这种细胞因子在调节肉芽肿反应中的作用。相反，用外源性rIL-12治疗显著抑制原发性肉芽肿形成，同时增加IFN-γ、IL-2、IL-10和IL-12肺mRNA水平并抑制IL-4、IL-5、IL-6和IL-13 mRNA表达。细胞因子耗竭研究表明，IL-12的作用可能主要归因于IFN-γ的增加。重要的是，IL-12还抑制了用鸡蛋预致敏的小鼠中的继发性肉芽肿形成，这表明细胞因子在逆转已建立的Th 2型反应中发挥了作用。此外，用鸡蛋与IL- 12联合致敏的小鼠在随后的鸡蛋攻击后仅产生最小的肉芽肿，以使它们预先向Th 1应答转化。后者的研究结果表明，同时接种抗原加IL-12可能提供了一种策略，用于预防嗜卵细胞病理学以及其他疾病源于Th 2细胞因子的生产。
Morbidity in humans infected with Schistosoma mansoni results primarily from the deposition of parasite eggs in portal areas where they induce a granulomatous response. In mice infected with this helminth granuloma formation is a CD4+ T helper (Th) cell-dependent process that is associated with a strong Th2 cytokine response which appears to evolve through a Th0 phase. In this report, we asked whether endogenously synthesized or exogenously induced interferon (IFN)gamma through its suppression of Th2 cell expansion exerts a regulatory role on egg pathology. Depletion of IFN-gamma or natural killer cells resulted in a marked enhancement of granuloma formation around intravenously injected eggs and was associated with increased Th2 and decreased Th1 and interleukin (IL)12 mRNA expression. Similar changes occurred when egg- injected mice were treated with neutralizing monoclonal antibodies specific for IL-12 indicating a role for this cytokine in the regulation of the granulomatous response. In contrast, treatment with exogenous rIL-12 profoundly inhibited primary granuloma formation while increasing IFN-gamma, IL-2, IL-10, and IL-12 pulmonary mRNA levels and suppressing IL-4, IL-5, IL-6, and IL-13 mRNA expression. Cytokine depletion studies indicated that the effects of IL-12 could be attributed primarily to increased IFN-gamma. Importantly, IL-12 also inhibited secondary granuloma formation in mice presensitized with eggs demonstrating a role for the cytokine in reversing established Th2-type responses. Moreover, mice sensitized with eggs in combination with IL- 12 to precommit them toward a Th1 response developed only minimal granulomas upon subsequent egg challenge. The latter findings suggest that simultaneous vaccination with antigen plus IL-12 may provide a strategy for the prevention of schistosome egg pathology as well as other diseases stemming from Th2 cytokine production.