Platelet Gene Therapy Promotes Targeted Peripheral Tolerance by Clonal Deletion and Induction of Antigen-Specific Regulatory T Cells.
Platelet Gene Therapy Promotes Targeted Peripheral Tolerance by Clonal Deletion and Induction of Antigen-Specific Regulatory T Cells.
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血小板基因疗法通过抗原特异性调节 T 细胞的克隆删除和诱导来促进靶向外周耐受
DOI：
10.3389/fimmu.2018.01950
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发表时间：
2018
影响因子：
7.3
通讯作者：
Shi Q
中科院分区：
文献类型：
--
作者：
Luo X;Chen J;Schroeder JA;Allen KP;Baumgartner CK;Malarkannan S;Hu J;Williams CB;Shi Q
基因治疗以及生物治疗剂的递送通常受到接受治疗的受试者的免疫应答的阻碍。我们已经报道了利用血小板作为载体的血友病有效基因治疗对治疗产品产生了深刻的耐受性。在这项研究中，我们研究了这种策略是否可以应用于诱导免疫耐受的非凝血蛋白，并探讨了免疫耐受诱导血小板靶向基因传递的基本机制。我们使用卵清蛋白（OVA）作为替代非凝血蛋白，并构建了慢病毒载体，其中OVA由血小板特异性αIIb启动子驱动。通过骨髓转导和移植引入血小板特异性OVA表达。95%以上的卵清蛋白储存在血小板α颗粒中。用OVA免疫的对照小鼠产生OVA特异性IgG抗体;然而，在血小板中表达OVA的小鼠不产生。此外，血小板中的OVA表达足以防止来自CAG-OVA小鼠的皮肤移植物的排斥，表明在血小板特异性OVA转导的受体中产生免疫耐受。为了评估参与这种耐受性的机制，我们使用了OTII小鼠，其表达对OVA衍生肽特异性的CD 4+效应T细胞。在血小板特异性OVA基因转移后，这些小鼠表现出T细胞的正常胸腺成熟，从而对抗中枢耐受。在外周，耐受性包括通过细胞凋亡和OVA特异性调节性T细胞群的扩增消除OVA特异性CD 4+效应T细胞。这些实验揭示了对血小板颗粒内容物的天然外周耐受过程的存在，所述血小板颗粒内容物可以被增选以递送治疗上重要的产物。
Delivery of gene therapy as well as of biologic therapeutics is often hampered by the immune response of the subject receiving the therapy. We have reported that effective gene therapy for hemophilia utilizing platelets as a delivery vehicle engenders profound tolerance to the therapeutic product. In this study, we investigated whether this strategy can be applied to induce immune tolerance to a non-coagulant protein and explored the fundamental mechanism of immune tolerance induced by platelet-targeted gene delivery. We used ovalbumin (OVA) as a surrogate non-coagulant protein and constructed a lentiviral vector in which OVA is driven by the platelet-specific αIIb promoter. Platelet-specific OVA expression was introduced by bone marrow transduction and transplantation. Greater than 95% of OVA was stored in platelet α-granules. Control mice immunized with OVA generated OVA-specific IgG antibodies; however, mice expressing OVA in platelets did not. Furthermore, OVA expression in platelets was sufficient to prevent the rejection of skin grafts from CAG-OVA mice, demonstrating that immune tolerance developed in platelet-specific OVA-transduced recipients. To assess the mechanism(s) involved in this tolerance we used OTII mice that express CD4+ effector T cells specific for an OVA-derived peptide. After platelet-specific OVA gene transfer, these mice showed normal thymic maturation of the T cells ruling against central tolerance. In the periphery, tolerance involved elimination of OVA-specific CD4+ effector T cells by apoptosis and expansion of an OVA-specific regulatory T cell population. These experiments reveal the existence of natural peripheral tolerance processes to platelet granule contents which can be co-opted to deliver therapeutically important products.
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影响因子：
20.3
作者：
Arruda, Valder R.;Doshi, Bhavya S.;Samelson-Jones, Benjamin J.
通讯作者：
Samelson-Jones, Benjamin J.
影响因子：
4.4
作者：
Ferguson, TA;Herndon, J;Green, DR
通讯作者：
Green, DR
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：
2.5
作者：
Festing, MFW
通讯作者：
Festing, MFW
影响因子：
12.4
作者：
Chen, Yingyu;Schroeder, Jocelyn A.;Shi, Qizhen
通讯作者：
Shi, Qizhen