Drug-dependent clearance of human platelets in the NOD/scid mouse by antibodies from patients with drug-induced immune thrombocytopenia
Drug-dependent clearance of human platelets in the NOD/scid mouse by antibodies from patients with drug-induced immune thrombocytopenia
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DOI：
10.1182/blood-2010-03-277764
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发表时间：
2010-10-21
期刊：
影响因子：
20.3
通讯作者：
Aster, Richard H.
中科院分区：
文献类型：
--
作者：
Bougie, Daniel W.;Nayak, Dhirendra;Aster, Richard H.
药物诱导的免疫性血小板减少症（DITP）是一种相对常见的，有时危及生命的疾病，由抗体引起，只有当药物存在时，抗体才会与血小板结合。药物依赖性抗体（DDAbs）是如何被诱导的，以及药物如何促进它们与血小板的相互作用还知之甚少，检测DDAbs的方法也不理想。DITP的小动物模型可以为解决这些和其他有关发病机制和诊断的问题提供新的工具。我们研究了非肥胖糖尿病/严重联合免疫缺陷（NOD/scid）小鼠，缺乏异种抗体，因此允许输注的人血小板循环，是否可以用于研究药物依赖性清除血小板的DDAbs在体内。在这份报告中，我们表明，NOD/SCID模型是适合于这一目的，并描述了研究，以优化其灵敏度的药物依赖性的人抗体检测。我们进一步表明，小鼠可以产生的代谢物的乙酰氨基-phen和napolipen的某些药物依赖性抗体是特定的数量足以使这些抗体引起血小板破坏。研究结果表明，NOD/scid小鼠可以为研究DITP发病机制提供一个独特的工具，并且对于鉴定能够引起免疫性血小板减少症或溶血性贫血的代谢物特异性抗体可能特别有价值。（血。2010;116（16）：3033-3038）
Drug-induced immune thrombocytopenia (DITP) is a relatively common and sometimes life-threatening condition caused by antibodies that bind avidly to platelets only when drug is present. How drug-dependent antibodies (DDAbs) are induced and how drugs promote their interaction with platelets are poorly understood, and methods for detecting DDAbs are suboptimal. A small animal model of DITP could provide a new tool for addressing these and other questions concerning pathogenesis and diagnosis. We examined whether the nonobese diabetic/severe combined immunodeficient (NOD/scid) mouse, which lacks xenoantibodies and therefore allows infused human platelets to circulate, can be used to study drug-dependent clearance of platelets by DDAbs in vivo. In this report, we show that the NOD/scid model is suitable for this purpose and describe studies to optimize its sensitivity for drug-dependent human antibody detection. We further show that the mouse can produce metabolites of acetamino-phen and naproxen for which certain drug-dependent antibodies are specific in quantities sufficient to enable these antibodies to cause platelet destruction. The findings indicate that the NOD/scid mouse can provide a unique tool for studying DITP pathogenesis and may be particularly valuable for identifying metabolite-specific antibodies capable of causing immune thrombocytopenia or hemolytic anemia. (Blood. 2010;116(16): 3033-3038)