Immune response against serial infusion of factor VIII antigen through an implantable venous-access device system in haemophilia A mice
Immune response against serial infusion of factor VIII antigen through an implantable venous-access device system in haemophilia A mice
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DOI：
10.1111/j.1365-2516.2011.02686.x
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发表时间：
2012-05-01
期刊：
影响因子：
3.9
通讯作者：
Sakata, Y.
中科院分区：
文献类型：
--
作者：
Madoiwa, S.;Kobayashi, E.;Sakata, Y.
.血友病A是一种终身出血性疾病，由遗传性缺乏因子VIII（FVIII）引起。约30%的血友病A患者在接受FVIII浓缩物治疗后产生中和抗体。用于根除抑制剂的免疫耐受方案需要每日静脉内递送FVIII。我们评估了预先免疫的血友病A小鼠对连续静脉注射FVIII的免疫应答。我们引入了一种可植入的静脉接入装置（iVAD）系统到血友病A小鼠，以促进FVIII的顺序输注。在用FVIII预免疫后，通过iVAD系统对血友病A小鼠进行FVIII的连续静脉内施用。在连续输注FVIII的所有小鼠中，在10个暴露日（ED）时产生高滴度的抗FVIII抑制性抗体。然而，连续低剂量输注FVIII [0.05 U g-1体重（BW），每周5次] 150 ED后，抗FVIII IgG滴度降低。与高剂量FVIII输注（0.5 U g-1 BW，每周5次）或预免疫小鼠相比，连续低剂量FVIII输注小鼠脾CD 4 + T细胞对体外FVIII刺激的免疫应答显著抑制。此外，连续低剂量输注FVIII的小鼠脾脏CD 4 + T细胞不能产生白细胞介素2和干扰素？。这些数据表明，连续输注FVIII可诱导具有抑制剂抗体的血友病A小鼠的T细胞无反应性。
. Haemophilia A is a life long bleeding disorder caused by an inherited deficiency of factor VIII (FVIII). About 30% of haemophilia A patients develop neutralizing antibodies as a consequence of treatment with FVIII concentrates. Immune tolerance protocols for the eradication of inhibitors require daily delivery of intravenous FVIII. We evaluated the immune responses to serial intravenous administration of FVIII in preimmunized haemophilia A mice. We introduced an implantable venous-access device (iVAD) system into haemophilia A mice to facilitate sequential infusion of FVIII. After preimmunization with FVIII, the haemophilia A mice were subjected to serial intravenous administration of FVIII through the iVAD system. In all mice with serial infusion of FVIII, high titers of anti-FVIII inhibitory antibodies developed at 10 exposure days (EDs). However, the anti-FVIII IgG titers were decreased after 150 EDs of sequential low-dose infusion of FVIII [0.05 U g-1 body weight (BW) five times per week]. Proliferative response to ex vivo FVIII stimulation was significantly suppressed in splenic CD4+ T cells from mice with serial low-dose FVIII infusion compared with those from mice with high-dose FVIII infusion (0.5 U g-1 BW five times per week) or preimmunized mice. Moreover, splenic CD4+ T cells from mice with serial low-dose infusion of FVIII failed to produce interleukin-2 and interferon-?. These data suggest that serial infusion of FVIII could induce T-cell anergy in haemophilia A mice with inhibitor antibodies.