Immune tolerance induced by platelet-targeted factor VIII gene therapy in hemophilia A mice is CD4 T cell mediated.
Immune tolerance induced by platelet-targeted factor VIII gene therapy in hemophilia A mice is CD4 T cell mediated.
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DOI：
10.1111/jth.13800
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发表时间：
2017-10
期刊：
影响因子：
--
通讯作者：
Shi Q
中科院分区：
文献类型：
--
作者：
Chen Y;Luo X;Schroeder JA;Chen J;Baumgartner CK;Hu J;Shi Q
免疫反应是基因治疗中的一个主要问题。我们前期的研究表明，血小板靶向FVIII(2bF8)基因治疗与体内转导细胞的药物选择相结合，可以挽救FVII小鼠的出血素质，诱导免疫耐受。目的：探讨非选择性2bF8慢病毒载体(LV)能否诱导免疫耐受，以及2bF8LV基因治疗后免疫耐受的诱导机制。通过2bF8LV转导和移植诱导血小板FVIII的表达。FVIII试验和尾部出血试验证实了血小板基因治疗的成功。用重组人F8攻击动物，探讨基因治疗后是否诱导免疫耐受。采用Treg细胞分析、T细胞增殖实验和记忆B细胞介导的ELISPOT实验研究免疫耐受的可能机制。结果表明，经2bF8LV基因治疗后，FVII小鼠的血小板FVIII持续表达，出血质量得以恢复。即使在rhF8攻击后，接受660cGy射线照射或白果加ATG处理的转导受体均未产生抗FVIII抑制抗体。转导2bF8LV的受者Treg细胞显著增加，形成的免疫耐受是可转移的。治疗动物的CD4+T细胞在重组人F8的再刺激下不能增殖，但在2bF8LV转导的受体中，记忆B细胞可以分化为抗体分泌细胞。2bF8LV基因转移可诱导血友病A小鼠产生免疫耐受，这种免疫耐受是由CD4+T细胞介导的。
Immune responses are a major concern in gene therapy. Our previous studies demonstrated that platelet-targeted FVIII (2bF8) gene therapy together with in vivo drug-selection of transduced cells can rescue the bleeding diathesis and induce immune tolerance in FVIIInull mice. To investigate whether non-selectable 2bF8 lentiviral vector (LV) for the induction of platelet-FVIII expression is sufficient to induce immune tolerance and how immune tolerance is induced after 2bF8LV gene therapy. Platelet-FVIII expression was introduced by 2bF8LV transduction and transplantation. FVIII assays and tail bleeding tests were use to confirm the success of platelet gene therapy. Animals were challenged with rhF8 to explore if immune tolerance was induced after gene therapy. Treg cell analysis, T cell proliferation assay, and memory B cell-mediated ELISPOT assay were used to investigate the potential mechanisms of immune tolerance. We showed that platelet-FVIII expression was sustained and the bleeding diathesis was restored in FVIIInull mice after 2bF8LV gene therapy. None of the transduced recipients developed anti-FVIII inhibitory antibodies in the groups preconditioned with 660 cGy irradiation or busulfan plus ATG treatment even after rhF8 challenge. Treg cells significantly increased in 2bF8LV-transduced recipients and the immune tolerance developed was transferable. CD4+ T cells from treated animals failed to proliferate in response to rhF8 restimulation, but memory B cells could differentiate into antibody secreting cells in 2bF8LV-transduced recipients. 2bF8LV gene transfer without in vivo selection of manipulated cells can introduce immune tolerance in hemophilia A mice and this immune tolerance is CD4+ T cell-mediated.
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影响因子：
32.4
作者：
Fontenot, JD;Rasmussen, JP;Rudensky, AY
通讯作者：
Rudensky, AY
影响因子：
--
作者：
Calcedo, Roberto;Morizono, Hiroki;Wilson, James M.
通讯作者：
Wilson, James M.
影响因子：
20.3
作者：
Lei, TC;Scott, DW
通讯作者：
Scott, DW
DOI：
10.1073/pnas.95.10.5734
发表时间：
1998-05-12
影响因子：
11.1
作者：
Evans, GL;Morgan, RA
通讯作者：
Morgan, RA
影响因子：
20.3
作者：
Martino, Ashley T.;Basner-Tschakarjan, Etiena;Herzog, Roland W.
通讯作者：
Herzog, Roland W.