Animal model of fetal and neonatal immune thrombocytopenia: role of neonatal Fc receptor in the pathogenesis and therapy

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)