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High-dose factor VIII inhibits factor VIII–specific memory B cells in hemophilia A with factor VIII inhibitors

机译:大剂量VIII因子通过VIII因子抑制剂抑制血友病A中的VIII因子特异性记忆B细胞

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摘要

Hemophilia A in its severe form is a life-threatening hemorrhagic disease that is caused by mutations in the factor VIII (FVIII) gene (symbol F8). About 25% of patients who receive replacement therapy develop neutralizing antibodies that inhibit the function of substituted FVIII. Long-term application of high doses of FVIII has evolved as an effective therapy to eradicate the antibodies and to induce long-lasting immune tolerance. Little is known, however, about the immunologic mechanisms that cause the down-modulation of anti-FVIII antibodies by high doses of FVIII. We report that high doses of FVIII inhibit the restimulation of FVIII-specific memory B cells and their differentiation into antibody-secreting plasma cells in vitro and in vivo in a murine model of hemophilia A. The inhibition of memory B-cell responses is irreversible and not mediated by FVIII-specific T cells. Furthermore, it seems to involve the activation of caspases. We conclude that the inhibition of FVIII-specific memory B cells might be an early event in the down-modulation of anti-FVIII antibodies in patients with hemophilia A who receive high doses of FVIII.
机译:严重的A型血友病是危及生命的出血性疾病,由VIII因子(FVIII)基因(符号F8)突变引起。约有25%接受替代疗法的患者会产生中和抗体,该抗体会抑制取代的FVIII的功能。长期应用高剂量的FVIII已经发展成为一种根除抗体并诱导持久免疫耐受的有效疗法。然而,关于通过高剂量的FVIII引起抗FVIII抗体下调的免疫机制知之甚少。我们报告高剂量的FVIII抑制血友病A鼠模型在体外和体内FVIII特异性记忆B细胞的再刺激及其分化成分泌抗体的浆细胞。对记忆B细胞反应的抑制是不可逆的,并且不受FVIII特异性T细胞介导。此外,它似乎涉及胱天蛋白酶的激活。我们得出结论,在接受大剂量FVIII的血友病A患者中,抑制FVIII特异性记忆B细胞可能是抗FVIII抗体下调的早期事件。

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