Induction of immune tolerance to coagulation factor IX antigen by in vivo hepatic gene transfer.
Induction of immune tolerance to coagulation factor IX antigen by in vivo hepatic gene transfer.
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DOI：
10.1172/jci16887
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发表时间：
2003-05
期刊：
影响因子：
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通讯作者：
F. Mingozzi;Yi-lin Liu;E. Dobrzynski;A. Kaufhold;Jian Hua Liu;Yuqin Wang;V. Arruda;K. High;R. Herzog
中科院分区：
文献类型：
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作者：
F. Mingozzi;Yi-lin Liu;E. Dobrzynski;A. Kaufhold;Jian Hua Liu;Yuqin Wang;V. Arruda;K. High;R. Herzog
基因替代疗法是治疗遗传病的一种有吸引力的方法，但可能会因中和治疗性基因产物的免疫反应而复杂化。有针对转基因产物的体液和细胞免疫反应的例子，以及没有这种反应的例子，这取决于载体设计和功能失调基因的潜在突变。然而，目前尚不清楚转基因表达是否可以诱导对治疗性抗原的耐受。在这里，我们展示了通过将腺相关病毒基因转移到肝脏来诱导对分泌型人凝血因子IX(hF.IX)抗原的免疫耐受。免疫耐受的小鼠在佐剂中加入hF.IX免疫后，没有抗hF.IX抗体，体外T细胞反应显著降低。耐受诱导是抗原特异性的，影响广泛的Th细胞亚群，并受启动子强度、载体剂量和小鼠品系决定的较高水平的转基因表达。肝细胞来源的hF.IX表达可诱导调节性CD4(+)T细胞，过继转移后可抑制抗hF.IX的形成。在菌株依赖的成功率下，在带有大量F.IX基因缺失的小鼠中诱导了对F.IX的耐受性，支持了这些数据与血友病B和其他遗传疾病治疗的相关性。
Gene replacement therapy is an attractive approach for treatment of genetic disease, but may be complicated by the risk of a neutralizing immune response to the therapeutic gene product. There are examples of humoral and cellular immune responses against the transgene product as well as absence of such responses, depending on vector design and the underlying mutation in the dysfunctional gene. It has been unclear, however, whether transgene expression can induce tolerance to the therapeutic antigen. Here, we demonstrate induction of immune tolerance to a secreted human coagulation factor IX (hF.IX) antigen by adeno-associated viral gene transfer to the liver. Tolerized mice showed absence of anti-hF.IX and substantially reduced in vitro T cell responses after immunization with hF.IX in adjuvant. Tolerance induction was antigen specific, affected a broad range of Th cell subsets, and was favored by higher levels of transgene expression as determined by promoter strength, vector dose, and mouse strain. Hepatocyte-derived hF.IX expression induced regulatory CD4(+) T cells that can suppress anti-hF.IX formation after adoptive transfer. With a strain-dependent rate of success, tolerance to murine F.IX was induced in mice with a large F.IX gene deletion, supporting the relevance of these data for treatment of hemophilia B and other genetic diseases.