Institute of Pharmacology and Toxicology, University of Zurich - Vetsuisse, Zurich, Switzerland.
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, USA.
Brain Behav Immun. 2019 Aug;80:406-418. doi: 10.1016/j.bbi.2019.04.019. Epub 2019 Apr 10.
Maternal immune activation (MIA) models that are based on administration of the viral mimetic, poly(I:C), are widely used as experimental tools to study neuronal and behavioral dysfunctions in relation to immune-mediated neurodevelopmental disorders and mental illnesses. Evidence from investigations in non-pregnant rodents suggests that different poly(I:C) products can vary in terms of their immunogenicity, even if they are obtained from the same vendor. The present study aimed at extending these findings to pregnant mice, while also controlling various poly(I:C) products for potential contamination with lipopolysaccharide (LPS). We found significant variability between different batches of poly(I:C) potassium salt obtained from the same vendor (Sigma-Aldrich) in terms of the relative amount of dsRNA fragments in the high molecular weight range (1000-6000 nucleotides long) and with regards to their effects on maternal thermoregulation and immune responses in maternal plasma, placenta and fetal brain. Batches of poly(I:C) potassium salt containing larger amounts of high molecular weight fragments induced more extensive effects on thermoregulation and immune responses compared to batches with minimal amounts of high molecular weight fragments. Consistent with these findings, poly(I:C) enriched for high molecular weight dsRNA (HMW) caused larger maternal and placental immune responses compared to low molecular weight (LMW) poly(I:C). These variable effects were unrelated to possible LPS contamination. Finally, we found marked variability between different batches of the poly(I:C) potassium salt in terms of their effects on spontaneous abortion rates. This batch-to-batch variability was confirmed by three independent research groups using distinct poly(I:C) administration protocols in mice. Taken together, the present data confirm that different poly(I:C) products can induce varying immune responses and can differentially affect maternal physiology and pregnancy outcomes. It is therefore pivotal that researchers working with poly(I:C)-based MIA models ascertain and consider the precise molecular composition and immunogenicity of the product in use. We recommend the establishment of reference databases that combine phenotype data with empirically acquired quality information, which can aid the design, implementation and interpretation of poly(I:C)-based MIA models.
母体免疫激活（MIA）模型基于病毒模拟物聚肌苷酸（polyinosinic:polycytidylic acid，poly(I:C)）的给药，被广泛用作研究与免疫介导的神经发育障碍和精神疾病相关的神经元和行为功能障碍的实验工具。来自非妊娠啮齿动物的研究证据表明，即使来自同一供应商，不同的 poly(I:C)产品在免疫原性方面也可能存在差异。本研究旨在将这些发现扩展到怀孕小鼠，同时还控制各种 poly(I:C)产品可能受到脂多糖（lipopolysaccharide，LPS）的污染。我们发现，来自同一供应商（Sigma-Aldrich）的不同批次的聚肌苷酸钾盐在高分子量范围（1000-6000 个核苷酸长）中双链 RNA 片段的相对含量以及对母体体温调节和母体血浆、胎盘和胎儿大脑免疫反应的影响方面存在显著差异。与含有最小量高分子量片段的批次相比，含有更多高分子量片段的聚肌苷酸钾盐批次诱导的体温调节和免疫反应更为广泛。与这些发现一致的是，与低分子量（low molecular weight，LMW）poly(I:C)相比，富含高分子量 dsRNA（high molecular weight，HMW）的 poly(I:C)引起更大的母体和胎盘免疫反应。这些可变效应与可能的 LPS 污染无关。最后，我们发现不同批次的聚肌苷酸钾盐在对自发流产率的影响方面存在显著差异。这一批次间的差异通过三个独立的研究小组在小鼠中使用不同的 poly(I:C)给药方案得到了证实。总之，本研究数据证实，不同的 poly(I:C)产品可以诱导不同的免疫反应，并可能对母体生理学和妊娠结局产生不同的影响。因此，使用 poly(I:C)-基于 MIA 模型的研究人员必须确定并考虑所使用产品的精确分子组成和免疫原性。我们建议建立参考数据库，将表型数据与经验获得的质量信息相结合，这有助于设计、实施和解释基于 poly(I:C)的 MIA 模型。
