Use of transient CD4 lymphocyte depletion to prolong transgene expression of E1-deleted adenoviral vectors.
Use of transient CD4 lymphocyte depletion to prolong transgene expression of E1-deleted adenoviral vectors.
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使用瞬时 CD4 淋巴细胞耗竭来延长 E1 缺失腺病毒载体的转基因表达。
DOI：
10.1089/hum.1996.7.4-489
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Shellito,JE
中科院分区：
文献类型：
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作者：
Kolls,JK;Lei,D;Odom,G;Nelson,S;Summer,WR;Gerber,MA;Shellito,JE
E1 缺失的腺病毒载体越来越多地用于体内基因转移。这些载体的潜在用途受到转基因瞬时表达和重新施用后转导率显着降低的限制，这可能是由于宿主对载体的免疫反应。我们假设 CD4+ 淋巴细胞是对这些载体产生免疫反应所必需的，并且消耗性抗 CD4 抗体 (GK1.5) 的施用可能会延长体内转基因表达。我们发现，与对照组相比，对小鼠进行单次注射（瞬时消除）或每周注射 GK1.5（持续消除）进行预处理，腺病毒编码的肿瘤坏死因子 (TNF) 抑制剂或荧光素酶基因的表达显着延长。此外，用GK1.5治疗的小鼠对重复施用该载体没有表现出抗腺病毒抗体反应，并且第二个腺病毒转基因可以在这些动物中表达。然而，对照小鼠产生了显着的中和抗体反应，通过施用第二种腺病毒来阻止转基因表达。这些发现表明，操纵宿主免疫反应可能会扩大利用腺病毒载体进行基因转移的潜在应用。
E1-deleted adenoviral vectors are increasingly being utilized forin vivogene transfer. The potential use of these vectors is limited by transient expression of the transgene and a markedly reduced rate of transduction following readministration, presumably due to a host immune response to the vector. We hypothesized that CD4+lymphocytes are necessary to generate an immune response to these vectors and that administration of a depleting anti-CD4 antibody (GK1.5) might prolong transgene expressionin vivo. We found that pretreatment of mice with a single injection (transient depletion) or weekly injections of GK1.5 (persistent depletion), markedly prolonged expression of an adenovirus-encoded tumor necrosis factor (TNF) inhibitor or luciferase gene compared to controls. Moreover, mice treated with GK1.5 showed no antiadenoviral antibody response to repeat administration of the vector and a second adenoviral transgene could be expressed in these animals. However, control mice developed a significant neutralizing antibody response that prevented transgene expression with administration of a second adenovirus. These findings demonstrate that manipulation of the host immune response may expand potential applications of gene transfer utilizing adenoviral vectors.