Nature、Science、Cell共探讨:实验室老鼠“脏”一点或许更好?
2016/04/22
4月20日,期刊《Nature》、《Cell Host & Microbe》同时在线发表两篇文章,共同围绕“实验室老鼠”、“野生老鼠”展开相关研究,并提出了新观点:“脏”老鼠或许可以更好地应用于生物基础和转化研究,它们或许将改变我们对全球卫生、慢性感染等疾病的研究模式。


谈及生物实验室培养的老鼠,多数都被安放在恒温恒湿、干净甚至于无菌室中,接受统一的处理和食物喂养。很明显,这与下水道、地洞、丛林等原生态环境有着极大反差。实验室老鼠被统一化饲养,是为了试验变量因素的可控制以及可重复性。但是,它也面临着一个关键问题:这种理想化条件下获得的动物试验数据,是否能够同理转化之临床?

4月20日,期刊《Nature》、《Cell Host & Microbe》同时在线发表了两篇文章,共同围绕“实验室老鼠”、“野生老鼠”展开相关研究,并提出了新观点:“脏”老鼠或许可以更好地应用于生物基础和转化研究,它们或许将改变我们对全球卫生、慢性感染等疾病的研究模式。

Nature:实验室老鼠与“脏”老鼠同居后,更“接地气”

无菌室培养的老鼠,它们的免疫系统都很简单,因为所处环境很少有机会被病毒、微生物等病原体感染,所以老鼠体内记忆T细胞无论在数量还是种类上,都远远少于野生老鼠。明尼苏达大学的免疫学家David Masopust却对这一“婴儿式的免疫平和”提出质疑,因为考虑到人类生活的环境更为复杂而多变,更何况如今环境污染、食品安全等问题越发多见,远远超过了实验室可控制的理想状态。


Masopust团队从宠物店采购野生老鼠,并把它们与无菌室里的老鼠放在一起喂养。他们认为,这些野生的“脏”老鼠会增强实验室老鼠的免疫系统,使其更接近于“成年人”化。

两种老鼠“同居”2个月后,22%的实验室老鼠死亡,其余存活下来的老鼠体内免疫机制却发生了很大变化。野生老鼠为实验室老鼠带来了病原体,从而使其血液中免疫相关分子种类显著增加,特别是T细胞。而且,实验室老鼠体内已经存在相关病毒、细菌、寄生虫的抗原。

同时,“同居”也改变了老鼠对抗细菌感染的方式:与野生老鼠接触后,实验室老鼠体内调动了超10000倍的免疫应答以防御单核细胞增生李斯特氏菌(Listeria monocytogenes)的感染。一系列变化意味着,实验室老鼠的免疫系统正朝着成年人的状态改变。

Masopust分析,经过上述处理后的老鼠更“接地气”,拥有更为现实的免疫机制。以此为模型进行动物试验能够获得更为准确的数据,从而为研发出更为高效、安全的新型药物和疫苗提供保障。他表示,未来,实验室老鼠接触复杂的病原体模拟人类可能会经历的环境是研究趋势。

Cell子刊:病毒、微生物感染实验室动物,会改变其免疫机制

无独有偶,来自于华盛顿大学的病毒免疫学家Skip Virgin也将研究视线投入到动物模型上。改变接触到的病原体是否会影响老鼠免疫机制?为了解答这一疑惑,他带领团队以疱疹病毒、流感病毒、寄生虫感染实验室老鼠,以验证黄热病疫苗在不同感染模型中的响应差异。

以上病毒、寄生虫普遍广泛存在与世界。如果它们的存在改变了疫苗的效用,那么将有助于我们理解为什么一些疫苗的有效性会存在地域差异。


以正常的实验室老鼠作为对照组,以病毒、微生物感染后的老鼠作为试验组,研究人员发现,试验初始两组老鼠对疫苗的免疫反应类似。但是,感染34天后,试验组老鼠体内的疫苗有效性却明显降低,血液中抗体数量逐渐减少。血液DNA测序结果显示两组老鼠与T细胞活力、细胞凋亡、免疫活性物质相关的基因表达模式出现差异。这些结果表明,病原体感染后的老鼠的免疫机制发生很大变化。

Virgin解释,Masopust团队的研究说明,野生的动物与实验室培养的动物,在免疫水平上存在本质不同。而Virgin团队 的最新成果则在其基础之上证实,在统一变量的情况下,通过感染特定病原体等处理,可以使得实验室老鼠的免疫系统朝着野生的老鼠,作出类似的改变。

然而,仅仅利用上述两项成果构建出能与人类免疫系统相媲美的老鼠模型仍然远远不够。其中,一个最大的挑战就是,改变的同时如何保证不破坏实验室老鼠原先的优势?不可否认,虽然不完美,但是实验室老鼠早已是众多生物实验室首选的研究模型了。无菌的环境、空白的免疫系统确保了全球实验室都能够统一变量和模型。

此外,一旦离开无菌环境,动物试验如何百分百重复也是问题。更何况,变量的增加无疑加重了构建、培养老鼠模型的时间、财力和物力。

推荐阅读

Can ‘dirty mice’ save animal research?

Dirty room-mates make lab mice more useful

所有文章仅代表作者观点,不代表本站立场。如若转载请联系原作者。
查看更多
  • Sequential Infection with Common Pathogens Promotes Human-like Immune Gene Expression and Altered Vaccine Response

    Immune responses differ between laboratory mice and humans. Chronic infection with viruses and parasites are common in humans, but are absent in laboratory mice, and thus represent potential contributors to inter-species differences in immunity. To test this, we sequentially infected laboratory mice with herpesviruses, influenza, and an intestinal helminth and compared their blood immune signatures to mock-infected mice before and after vaccination against yellow fever virus (YFV-17D). Sequential infection altered pre- and post-vaccination gene expression, cytokines, and antibodies in blood. Sequential pathogen exposure induced gene signatures that recapitulated those seen in blood from pet store-raised versus laboratory mice, and adult versus cord blood in humans. Therefore, basal and vaccine-induced murine immune responses are altered by infection with agents common outside of barrier facilities. This raises the possibility that we can improve mouse models of vaccination and immunity by selective microbial exposure of laboratory animals to mimic that of humans.

    展开 收起
  • Normalizing the environment recapitulates adult human immune traits in laboratory mice

    Our current understanding of immunology was largely defined in laboratory mice, partly because they are inbred and genetically homogeneous, can be genetically manipulated, allow kinetic tissue analyses to be carried out from the onset of disease, and permit the use of tractable disease models. Comparably reductionist experiments are neither technically nor ethically possible in humans. However, there is growing concern that laboratory mice do not reflect relevant aspects of the human immune system, which may account for failures to translate disease treatments from bench to bedside1, 2, 3, 4, 5, 6, 7, 8. Laboratory mice live in abnormally hygienic specific pathogen free (SPF) barrier facilities. Here we show that standard laboratory mouse husbandry has profound effects on the immune system and that environmental changes produce mice with immune systems closer to those of adult humans. Laboratory mice—like newborn, but not adult, humans—lack effector-differentiated and mucosally distributed memory T cells. These cell populations were present in free-living barn populations of feral mice and pet store mice with diverse microbial experience, and were induced in laboratory mice after co-housing with pet store mice, suggesting that the environment is involved in the induction of these cells. Altering the living conditions of mice profoundly affected the cellular composition of the innate and adaptive immune systems, resulted in global changes in blood cell gene expression to patterns that more closely reflected the immune signatures of adult humans rather than neonates, altered resistance to infection, and influenced T-cell differentiation in response to a de novo viral infection. These data highlight the effects of environment on the basal immune state and response to infection and suggest that restoring physiological microbial exposure in laboratory mice could provide a relevant tool for modelling immunological events in free-living organisms, including humans.

    展开 收起
发表评论 我在frontend\modules\comment\widgets\views\文件夹下面 test