Use of Humanized Mice to Study the Pathogenesis of Autoimmune and Inflammatory Diseases.
Use of Humanized Mice to Study the Pathogenesis of Autoimmune and Inflammatory Diseases.
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DOI：
10.1097/mib.0000000000000446
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发表时间：
2015-07
影响因子：
4.9
通讯作者：
Grisham MB
中科院分区：
文献类型：
--
作者：
Koboziev I;Jones-Hall Y;Valentine JF;Webb CR;Furr KL;Grisham MB
在过去的几十年里，研究界广泛使用疾病的动物模型，以更好地了解不同疾病的发病机制，并评估不同治疗药物的疗效和毒性。使用急性和慢性炎症性疾病的小鼠模型对许多临床前干预研究进行的回顾性分析揭示了将有希望的干预或治疗转化为患者临床有效治疗的普遍失败。尽管已经提出了几个可能的原因来解释这种将治疗功效从实验室工作台转化到患者床边的普遍失败，但越来越明显的是，小鼠免疫系统可能无法充分概括在人类疾病中观察到的免疫病理学机制。事实上，众所周知，小鼠和人类免疫学之间存在>80个主要差异;所有这些差异都导致免疫系统发育、激活和对先天性和适应性免疫中的挑战的应答的显著差异。这种不方便的现实促使研究人员试图使小鼠免疫系统人性化，以解决不可能在患者中研究的重要的人类特异性问题。人血淋巴细胞在小鼠中的成功长期移植将为研究者提供一种相对便宜的小动物模型，以研究临床相关机制，并促进体内人类特异性治疗的评估。淋巴细胞减少小鼠中IL-2受体共同γ链的靶向突变允许功能性人免疫细胞的长期植入的发现极大地提高了我们使小鼠免疫系统人源化的能力。这篇综述的目的是提出一个简短的概述，已在开发和使用的人源化小鼠，特别强调自身免疫性和慢性炎症性疾病的最新进展。此外，我们讨论了当前的挑战和可能的解决方案，利用这些独特的小鼠模型来定义负责慢性肠道炎症的诱导和持续的人类特异性免疫病理机制。
Animal models of disease have been used extensively by the research community for the past several decades to better understand the pathogenesis of different diseases as well as assess the efficacy and toxicity of different therapeutic agents. Retrospective analyses of numerous preclinical intervention studies using mouse models of acute and chronic inflammatory diseases reveal a generalized failure to translate promising interventions or therapeutics into clinically-effective treatments in patients. Although several possible reasons have been suggested to account for this generalized failure to translate therapeutic efficacy from the laboratory bench to the patient’s bedside, it is becoming increasingly apparent that the mouse immune system may not adequately recapitulate the immuno-pathological mechanisms observed in human diseases. Indeed, it is well-known that >80 major differences exist between mouse and human immunology; all of which contribute to significant differences in immune system development, activation and responses to challenges in innate and adaptive immunity. This inconvenient reality has prompted investigators to attempt to humanize the mouse immune system in order to address important, human-specific questions that are impossible to study in patients. The successful long-term engraftment of human hemato-lymphoid cells in mice would provide investigators with a relatively inexpensive, small animal model to study clinically-relevant mechanisms as well as facilitate the evaluation of human-specific therapies in vivo. The discovery that targeted mutation of the IL-2 receptor common gamma chain in lymphopenic mice allows for the long-term engraftment of functional human immune cells has advanced greatly our ability to humanize the mouse immune system. The objective of this review is to present a brief overview of the recent advances that have been made in the development and use of humanized mice with special emphasis on autoimmune and chronic inflammatory diseases. In addition, we discuss current challenges and possible solutions for utilizing these unique mouse models to define the human-specific immuno-pathological mechanisms responsible for the induction and perpetuation of chronic gut inflammation.