Huang L, Krieg A M, Eller N, Scott D E
Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, Maryland 20892, USA.
Infect Immun. 1999 Dec;67(12):6257-63. doi: 10.1128/IAI.67.12.6257-6263.1999.
Th1 immune responses, characterized by production of gamma interferon (IFN-gamma), are associated with protective immunity to viruses and intracellular bacteria. Heat-killed Brucella abortus promotes secretion of Th1-inducing cytokines such as interleukin-12 (IL-12) and IFN-gamma and has been used as a carrier to induce Th1 responses to vaccines. To explore which bacterial constituents could mediate this response and how it is regulated, murine spleen cells were cultured with B. abortus derived DNA, lipopolysaccharide (LPS), or whole killed organisms. Each constituent induced similar, substantial amounts of IL-10. However, only B. abortus and B. abortus DNA induced high levels of IFN-gamma and IL-12. B. abortus and B. abortus DNA-stimulated IL-12 production was maximal by 6 to 18 h, while IL-10 production steadily accumulated over this time period. These kinetics suggested that IL-10 may eventually downmodulate the Th1-like cytokine response to B. abortus and B. abortus DNA, which was confirmed by using neutralizing antibody. In the absence of IL-10, B. abortus LPS induced strong IFN-gamma responses, but IL-12 p70 levels were still undetectable from BALB/c spleen cells. LPS induced IL-12 if the spleen cells were primed with IFN-gamma and IL-10 was neutralized, indicating that LPS can stimulate IL-12 production under the most favorable conditions. Responses to Escherichia coli LPS and DNA mirrored the responses to B. abortus components, suggesting that immune effects observed with these constituents may be generalizable to many microbial species. In vivo experiments demonstrated the same hierarchy of responses for IL-12 production. These findings support the likelihood that microbial components, if used as carriers or adjuvants, can differ substantially in their ability to effect a Th1 response.
以γ干扰素（IFN-γ）产生为特征的Th1免疫反应与对病毒和细胞内细菌的保护性免疫相关。热灭活的流产布鲁氏菌可促进Th1诱导细胞因子如白细胞介素-12（IL-12）和IFN-γ的分泌，并已被用作诱导针对疫苗的Th1反应的载体。为了探索哪些细菌成分可以介导这种反应以及它是如何被调节的，将小鼠脾细胞与流产布鲁氏菌衍生的DNA、脂多糖（LPS）或全灭活生物体一起培养。每种成分都诱导产生了相似的大量IL-10。然而，只有流产布鲁氏菌和流产布鲁氏菌DNA诱导了高水平的IFN-γ和IL-12。流产布鲁氏菌和流产布鲁氏菌DNA刺激的IL-12产生在6至18小时达到最大值，而IL-10产生在这段时间内稳步积累。这些动力学表明IL-10最终可能下调对流产布鲁氏菌和流产布鲁氏菌DNA的Th1样细胞因子反应，这通过使用中和抗体得到了证实。在没有IL-10的情况下，流产布鲁氏菌LPS诱导了强烈的IFN-γ反应，但从BALB/c脾细胞中仍检测不到IL-12 p70水平。如果脾细胞用IFN-γ预处理且IL-10被中和，LPS可诱导IL-12产生，这表明LPS在最有利的条件下可刺激IL-12产生。对大肠杆菌LPS和DNA的反应反映了对流产布鲁氏菌成分的反应，表明用这些成分观察到的免疫效应可能适用于许多微生物物种。体内实验证明了IL-12产生的相同反应层次。这些发现支持了这样一种可能性，即微生物成分如果用作载体或佐剂，在影响Th1反应的能力上可能有很大差异。
