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1、免疫性血小板减少性紫癜动物模型的研究进展【摘要】 免疫性血小板减少性紫癜是一种较为常见的自身免疫病，其临床试验多建立于临床药物的应用，而非亚临床研究，有可能因为意外并发症被迫中止，因此建立理想的动物模型有助于加深对ITP发病机制和用药机理的理解。本综述回顾了ITP模型的发展过程，总结了被动型和主动型造模方法在ITP研究中的应用，尤其是转基因小鼠可更好模拟人类疾病病理状态，有利于进一步探讨新的诊断和治疗方法。【关键词】 免疫性血小板减少性紫癜Progress of Studies on Animal Model of immune thrombocytopenic purpura ReviewA
2、bstract Human ITP clinical trials have been performed based on observations of clinical uses of drugs，other than on mechanism studies in preclinical models，many studies were stopped because of unexpected complications. So there was need to develop ideal animal model of ITP to improve the understandi
3、ng of the pathophysiology and the mechanisms of action of therapeutics. In this review，the history of animal models of ITP was retrospected，two modeling methods inducing passive and active models，especially transgenic rice model which can more accurately represent human disease pathophysiology，and t
4、heir application in study of ITP were summarized. An animal model for human immune thrombocytopenia allows detailed studies of the mechanism，kinetics，and therapy of human immune thrombocytopenia.Key words immune thrombocytopenic purpura; autoantibody; animal model 目前人类免疫性血小板减少性紫癜的临床试验多建立在临床药物应用的基础上，
5、而不是亚临床研究。这样的试验有可能因为出现意外并发症而被迫中止。试验中，小鼠血小板GP的单克隆抗体被注入野生小鼠体内后引起了免疫性血小板减少症。Clynes等19观察到敲除FcR链的小鼠血小板数量没有减少。FcRIIa转基因小鼠当注射了血小板抗体后也出现了明显的血小板减少症。此外，FcR-链敲除后，FcRIIa基因及其自身能够介导明显的免疫性血小板减少症20。由此得出结论，如果想让鼠类免疫性血小板减少症的模型能够更精确地模拟人类的疾病的情况，FcRIIa基因一定要存在21。 最近，McKenzie等22首创性地将人类FcRIIa基因转导入自发自身免疫的主动型ITP模型中。雌性NZW鼠同BXSB
6、雄性鼠相交配后，雄性F1发生了系统性自身免疫性疾病，系统性自身免疫性疾病，包括继发于血小板自身抗体的免疫性血小板减少症。杂交第一代小鼠的免疫性血小板减少症能够通过脾切除得到改善。血小板减少在杂交第一代雄性带有FcRIIa基因表达的小鼠中比缺少FcRIIa基因表达的小鼠表现更为严重。 McKenzie等23还将FcRIIA 转基因鼠与 FcR 敲除小鼠进行交配，检测FcRIIA在FcRI 及FcRIII缺失的情况下发挥的免疫清除作用，结果出现严重的免疫性血小板减少，证实了FcRIIA在体内免疫清除中发挥着重要作用。除外先前在被动动物模型中的描述，这些在主动型动物模型中的结果证实，FcRIIa在体
7、内自身免疫性血小板减少症中是一个重要的受体。 其他关于构建ITP小鼠模型的方法很多，包括通过干细胞移植使小鼠表达人类血小板抗原，如人类糖蛋白GPb-a等，但目前研究仍较少24。相信通过大鼠和小鼠模型来阐明ITP发病机制及治疗机理已经取得了实质性进展，通过实验对各方面因素进行合适的调整，有望建立一个理想的、稳定的、可操作性好的、能尽可能地模拟人体状态的动物模型，为研究ITP的发病机制和药物治疗机理提供可行性。【参考文献】 1Iki S，Urabe A. Refractory idiopathic thrombocytopenic purpura. Nippon Rinsho. 2003，61:
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