Prevention and Reversal of Antibody Responses Against Factor IX in Gene Therapy for Hemophilia B.
Prevention and Reversal of Antibody Responses Against Factor IX in Gene Therapy for Hemophilia B.
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DOI：
10.3389/fmicb.2011.00244
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发表时间：
2011
影响因子：
5.2
通讯作者：
Herzog RW
中科院分区：
文献类型：
--
作者：
Nayak S;Sarkar D;Perrin GQ;Moghimi B;Hoffman BE;Zhou S;Byrne BJ;Herzog RW
肌肉注射(IM)腺相关病毒(AAV)载体是治疗X连锁出血性疾病血友病B(FIX，F.IX，缺乏症)的一种简单而安全的基因转移方法。然而，这种方法受到针对F.IX的免疫反应风险增加的阻碍。此前，我们证明了免疫抑制剂雷帕霉素、IL-10和特定多肽(编码主要的CD4+T细胞表位)的药物鸡尾酒可以诱导调节性T细胞(Treg)，伴随着抗原特异性效应T细胞的凋亡(Nayak等人，)。该方案能有效地防止肌肉基因转移到C3H/HeJ血友病B小鼠(靶向F9基因缺失)过程中抗人F.IX(hF.IX)抗体的形成。在这里，我们表明，该协议也可以用于逆转抑制剂的形成。肌注AAV1-hF.IX载体后，1个 月内平均可抑制8~10 BU。随后用耐受性鸡尾酒进行治疗后，hF.IX特异性抗体迅速减少到<；2 BU，持续了>；4.5 个月。全身性hF.IX表达从检测不到增加到>；200 ng/ml，凝血时间得到改善。此外，我们开发了一种不需要T细胞表位知识的针对抑制剂形成的替代预防方案，包括每天口服雷帕霉素1个月，结合频繁、低剂量静脉注射hF.IX蛋白。在T细胞受体转基因小鼠上的实验表明，给药途径和给药程序对Treg的诱导有很大影响。当联合静脉注射抗原时，必须每天口服雷帕霉素以诱导Treg，其抑制作用和表型与自然Treg相似。
Intramuscular (IM) administration of an adeno-associated viral (AAV) vector represents a simple and safe method of gene transfer for treatment of the X-linked bleeding disorder hemophilia B (factor IX, F.IX, deficiency). However, the approach is hampered by an increased risk of immune responses against F.IX. Previously, we demonstrated that the drug cocktail of immune suppressants rapamycin, IL-10, and a specific peptide (encoding a dominant CD4+ T cell epitope) caused an induction of regulatory T cells (Treg) with a concomitant apoptosis of antigen-specific effector T cells (Nayak et al.,). This protocol was effective in preventing inhibitory antibody formation against human F.IX (hF.IX) in muscle gene transfer to C3H/HeJ hemophilia B mice (with targeted F9 gene deletion). Here, we show that this protocol can also be used to reverse inhibitor formation. IM injection of AAV1–hF.IX vector resulted in inhibitors of on average 8–10 BU within 1 month. Subsequent treatment with the tolerogenic cocktail accomplished a rapid reduction of hF.IX-specific antibodies to <2 BU, which lasted for >4.5 months. Systemic hF.IX expression increased from undetectable to >200 ng/ml, and coagulation times improved. In addition, we developed an alternative prophylactic protocol against inhibitor formation that did not require knowledge of T cell epitopes, consisting of daily oral administration of rapamycin for 1-month combined with frequent, low-dose intravenous injection of hF.IX protein. Experiments in T cell receptor transgenic mice showed that the route and dosing schedule of drug administration substantially affected Treg induction. When combined with intravenous antigen administration, oral delivery of rapamycin had to be performed daily in order to induce Treg, which were suppressive and phenotypically comparable to natural Treg.
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DOI：
10.1073/pnas.0705863104
发表时间：
2007-08-07
影响因子：
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