Adenosine deaminase-deficient mice generated using a two-stage genetic engineering strategy exhibit a combined immunodeficiency
Adenosine deaminase-deficient mice generated using a two-stage genetic engineering strategy exhibit a combined immunodeficiency
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DOI：
10.1074/jbc.273.9.5093
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发表时间：
1998-02-27
影响因子：
4.8
通讯作者：
Kellems, RE
中科院分区：
文献类型：
--
作者：
Blackburn, MR;Datta, SK;Kellems, RE
腺苷脱氨酶（ADA）缺乏导致人类联合免疫缺陷。由于无法获得用于详细分析的人体组织以及缺乏适当的疾病动物模型，因此尚未完全了解该疾病的淋巴特异性所涉及的机制。我们报告了使用两阶段基因工程策略来产生ADA缺陷小鼠，这些小鼠保留了与人类ADA缺陷相关的许多特征，包括联合免疫缺陷。严重的T和B细胞淋巴细胞减少症伴随着胸腺和脾脏中2 '-脱氧腺苷和dATP的显著蓄积，以及这些器官中S-腺苷高半胱氨酸水解酶的显著抑制。腺苷蓄积在所有检查的组织中广泛存在。ADA缺陷小鼠也表现出严重的肺功能不全，骨异常，和肾脏发病机制。这些小鼠为与ADA缺乏相关的免疫表型的代谢基础提供了体内信息。
Adenosine deaminase (ADA) deficiency in humans leads to a combined immunodeficiency. The mechanisms involved in the lymphoid specificity of the disease are not fully understood due to the inaccessibility of human tissues for detailed analysis and the absence of an adequate animal model for the disease. We report the use of a two-stage genetic engineering strategy to generate ADA-deficient mice that retain many features associated with ADA deficiency in humans, including a combined immunodeficiency. Severe T and B cell lymphopenia was accompanied by a pronounced accumulation of 2'-deoxyadenosine and dATP in the thymus and spleen, and a marked inhibition of S-adenosylhomocysteine hydrolase in these organs, Accumulation of adenosine was widespread among all tissues examined. ADA-deficient mice also exhibited severe pulmonary insufficiency, bone abnormalities, and kidney pathogenesis. These mice have provided in vivo information into the metabolic basis for the immune phenotype associated with ADA deficiency.