Recombinant interleukin 12 cures mice infected with Leishmania major.
Recombinant interleukin 12 cures mice infected with Leishmania major.
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重组白介素12治愈感染了利什曼原虫大调的小鼠。
DOI：
10.1084/jem.177.5.1505
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发表时间：
1993-05-01
影响因子：
15.3
通讯作者：
Gately, M K
中科院分区：
文献类型：
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作者：
Heinzel, F P;Schoenhaut, D S;Rerko, R M;Rosser, L E;Gately, M K
感染利什曼原虫的耐药C57 BL/6小鼠可自愈，而敏感的BALB/c小鼠无法控制皮肤感染，随后发生致命的内脏传播。这些不同的结果介导的不同扩增的辅助性T细胞1型（Th 1）和Th 2的CD 4 + T淋巴细胞亚群在体内治疗和疾病的进展。由于白细胞介素12（IL-12）具有强效的T细胞生长和干扰素γ（IFN-γ）刺激作用，我们研究了其对小鼠利什曼病期间CD 4 + T细胞分化的影响。在感染的第一周内用重组鼠（rMu）IL-12治疗治愈了89%的正常易感BALB/c小鼠，定义为感染足垫尺寸减小和寄生虫负荷减少1，000 - 10，000倍，并提供了对再感染的持久抵抗力。治愈与抗原或有丝分裂原培养的淋巴结细胞产生IL-4的显著抑制有关，但相对于未治疗的小鼠，IFN-γ的产生保持或增加。与从感染的淋巴结分离的CD 4 + T淋巴细胞相关的IL-4和IFN-γ mRNA显示出响应于rMuIL-12治疗的类似的相互变化。单次注射抗IFN-γ单克隆抗体消除了rMuIL-12疗法的保护作用并恢复了Th 2细胞因子应答。我们得出结论，rMuIL-12防止有害的Th 2 T细胞反应，并促进治疗性Th 1反应，在IFN-γ依赖的方式在鼠利什曼病。由于BALB/c利什曼病不能用单独的rMuIFN-γ治愈，因此提示IL-12在T细胞亚群选择期间的额外直接作用。由于rMuIL-12在这种充分表征的慢性寄生模型中具有独特的保护作用，IL-12产生的差异可能是宿主对L.主要和其他细胞内病原体。
Resistant C57BL/6 mice infected with Leishmania major are self-healing, whereas susceptible BALB/c mice fail to contain cutaneous infection and subsequently undergo fatal visceral dissemination. These disparate outcomes are mediated by dissimilar expansions of T helper type 1 (Th1) and Th2 CD4+ T lymphocyte subsets in vivo during cure and progression of disease. Because interleukin 12 (IL-12) has potent T cell growth and interferon gamma (IFN-gamma) stimulatory effects, we studied its effect on CD4+ T cell differentiation during murine leishmaniasis. Treatment with recombinant murine (rMu)IL-12 during the first week of infection cured 89% of normally susceptible BALB/c mice, as defined by decreased size of infected footpads and 1,000-10,000-fold reduced parasite burdens, and provided durable resistance against reinfection. Cure was associated with markedly depressed production of IL-4 by lymph node cells cultured with antigen or mitogen, but preserved or increased production of IFN-gamma relative to untreated mice. IL-4 and IFN-gamma mRNA associated with CD4+ T lymphocytes isolated from infected lymph nodes showed similar reciprocal changes in response to rMuIL-12 therapy. A single injection of anti-IFN-gamma monoclonal antibody abrogated the protective effect of rMuIL-12 therapy and restored Th2 cytokine responses. We conclude that rMuIL-12 prevents deleterious Th2 T cell responses and promotes curative Th1 responses in an IFN-gamma- dependent fashion during murine leishmaniasis. Since BALB/c leishmaniasis cannot be cured with rMuIFN-gamma alone, additional direct effects of IL-12 during T cell subset selection are suggested. Because rMuIL-12 is uniquely protective in this well-characterized model of chronic parasitism, differences in IL-12 production may underlie heterogenous host responses to L. major and other intracellular pathogens.