Insulin B chain 9-23 gene transfer to hepatocytes protects from type 1 diabetes by inducing Ag-specific FoxP3+ Tregs
Insulin B chain 9-23 gene transfer to hepatocytes protects from type 1 diabetes by inducing Ag-specific FoxP3+ Tregs
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DOI：
10.1126/scitranslmed.aaa3032
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发表时间：
2015-05-27
影响因子：
17.1
通讯作者：
Roncarolo, Maria Grazia
中科院分区：
文献类型：
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作者：
Akbarpour, Mahzad;Goudy, Kevin S.;Roncarolo, Maria Grazia
人类1型糖尿病（T1D）抗原特异性耐受性尚未实现。将慢病毒载体（LV）介导的基因表达靶向肝细胞诱导对编码Ag的主动耐受。胰岛素B链9-23 （InsB(9-23)）是非肥胖糖尿病（NOD）小鼠的免疫显性T细胞表位。为了确定auto-Ag基因转移到肝细胞是否会诱导T1D的耐受和控制，我们用整合酶活性的LVs （ICLVs）治疗NOD小鼠，这些LVs选择性地靶向InsB（9-23）在肝细胞中的表达。ICLV处理诱导InsB（9-23）特异性效应T细胞和FoxP3（+）调节性T细胞（T-regs），其阻止胰岛免疫细胞浸润，并保护T1D。此外，ICLV治疗联合单一次优剂量的抗cd3单克隆抗体（mAb）对T1D逆转有效。左室脾细胞。InsB（9-23）处理小鼠，但不来自LV。卵清蛋白（OVA）治疗的对照小鼠，阻止了糖尿病的发展，表明这种保护是ag特异性的。CD4(+) D25(+)FoxP3(+) T细胞耗竭导致糖尿病进展，表明ag特异性FoxP3(+) T-regs介导了保护作用。整合酶缺陷lv （idlv）。InsB（9-23）减轻了对插入突变的担忧，并支持肝细胞中的瞬时转基因表达，也能有效保护T1D。这些数据表明，肝细胞靶向的auto-Ag基因表达可以预防和解决T1D，而这种保护并不需要转基因的稳定整合。基因转移到肝细胞可用于自身免疫性疾病诱导ag特异性耐受性。
Antigen (Ag)-specific tolerance in type 1 diabetes (T1D) in human has not been achieved yet. Targeting lentiviral vector (LV)-mediated gene expression to hepatocytes induces active tolerance toward the encoded Ag. The insulin B chain 9-23 (InsB(9-23)) is an immunodominant T cell epitope in nonobese diabetic (NOD) mice. To determine whether auto-Ag gene transfer to hepatocytes induces tolerance and control of T1D, NOD mice were treated with integrase-competent LVs (ICLVs) that selectively target the expression of InsB(9-23) to hepatocytes. ICLV treatment induced InsB(9-23)-specific effector T cells but also FoxP3(+) regulatory T cells (T-regs), which halted islet immune cell infiltration, and protected from T1D. Moreover, ICLV treatment combined with a single suboptimal dose of anti-CD3 monoclonal antibody (mAb) is effective in T1D reversal. Splenocytes from LV. InsB(9-23)-treated mice, but not from LV. OVA (ovalbumin)-treated control mice, stopped diabetes development, demonstrating that protection is Ag-specific. Depletion of CD4(+) D25(+)FoxP3(+) T cells led to diabetes progression, indicating that Ag-specific FoxP3(+) T-regs mediate protection. Integrase-defective LVs (IDLVs). InsB(9-23), which alleviate the concerns for insertional mutagenesis and support transient transgene expression in hepatocytes, were also efficient in protecting from T1D. These data demonstrate that hepatocyte-targeted auto-Ag gene expression prevents and resolves T1D and that stable integration of the transgene is not required for this protection. Gene transfer to hepatocytes can be used to induce Ag-specific tolerance in autoimmune diseases.