Animal model of fetal and neonatal immune thrombocytopenia: role of neonatal Fc receptor in the pathogenesis and therapy
Animal model of fetal and neonatal immune thrombocytopenia: role of neonatal Fc receptor in the pathogenesis and therapy
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DOI：
10.1182/blood-2010-05-284919
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发表时间：
2010-11-04
期刊：
影响因子：
20.3
通讯作者：
Ni, Heyu
中科院分区：
文献类型：
--
作者：
Chen, Pingguo;Li, Conglei;Ni, Heyu
胎儿和新生儿免疫性血小板减少症（FNIT）是一种严重的出血性疾病，其中母体抗体穿过胎盘并破坏胎儿/新生儿血小板。研究表明新生儿Fc受体（FcRn）调节免疫球蛋白G（IgG）的稳态并在IgG的经胎盘转运中起重要作用。然而，FcRn在FNIT的发病机制和治疗中的作用尚未研究。在这里，我们开发了一个FNIT的动物模型，使用组合β 3整合素缺陷和FcRn缺陷（β 3（-/-）FcRn（-/-））小鼠。我们发现β 3（-/-）FcRn（-/-）小鼠对β 3（+/+）FcRn（-/-）血小板有免疫应答。产生的抗体是β 3整联蛋白特异性的，并维持在成年β 3（+/+）FcRn（-/-）小鼠中有效诱导血小板减少症的水平。当免疫的β 3（-/-）FcRn（+/+）雌性与β 3（+/+）FcRn（+/+）雄性交配时，观察到FNIT，而在与β 3（+/+）FcRn（-/-）雄性交配的β 3（-/-）FcRn（-/-）雌性中未发生FNIT，表明FcRn对于诱导FNIT是不可缺少的。我们进一步证明了胎儿FcRn负责各种IgG同种型的经胎盘转运。我们发现，抗FcRn抗体和静脉注射IgG预防FNIT，静脉注射IgG通过FcRn依赖性和非依赖性途径改善FNIT。我们的数据表明，靶向FcRn可能是人类FNIT以及其他母体致病性抗体介导的疾病的潜在疗法。（血。2010;116（18）：3660-3668）
Fetal and neonatal immune thrombocytopenia (FNIT) is a severe bleeding disorder in which maternal antibodies cross the placenta and destroy fetal/neonatal platelets. It has been demonstrated that the neonatal Fc receptor (FcRn) regulates immunoglobulin G (IgG) homeostasis and plays an important role in transplacental IgG transport. However, the role of FcRn in the pathogenesis and therapy of FNIT has not been studied. Here, we developed an animal model of FNIT using combined beta 3 integrin-deficient and FcRn-deficient (beta 3(-/-)FcRn(-/-)) mice. We found that beta 3(-/-)FcRn(-/-) mice are immunoresponsive to beta 3(+/+)FcRn(-/-) platelets. The generated antibodies were beta 3 integrin specific and were maintained at levels that efficiently induced thrombocytopenia in adult beta 3(+/+)FcRn(-/-) mice. FNIT was observed when immunized beta 3(-/-)FcRn(+/+) females were bred with beta 3(+/+)FcRn(+/+) males, while no FNIT occurred in beta 3(-/-)FcRn(-/-) females bred with beta 3(+/+)FcRn(-/-) males, suggesting that FcRn is indispensable for the induction of FNIT. We further demonstrated that fetal FcRn was responsible for the transplacental transport of various IgG isotypes. We found that anti-FcRn antibody and intravenous IgG prevented FNIT, and that intravenous IgG ameliorated FNIT through both FcRn-dependent and -independent pathways. Our data suggest that targeting FcRn may be a potential therapy for human FNIT as well as other maternal pathogenic antibody-mediated diseases. (Blood. 2010;116(18):3660-3668)