Successful attenuation of humoral immunity to viral capsid and transgenic protein following AAV-mediated gene transfer with a non-depleting CD4 antibody and cyclosporine.
Successful attenuation of humoral immunity to viral capsid and transgenic protein following AAV-mediated gene transfer with a non-depleting CD4 antibody and cyclosporine.
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作者：
评价了使用非消耗性抗CD 4（NDCD 4）抗体和环孢菌素（CyA）组合的瞬时免疫抑制消除对腺相关病毒载体（AAV）及其转基因产物的免疫反应性的能力。在向免疫活性小鼠静脉内施用2×1012 AAV 8载体颗粒/kg后，这种免疫抑制剂的组合导致所得抗AAV 8抗体滴度降低20倍至未处理小鼠中的水平。这允许在用相同衣壳假型化的载体进行二次攻击时有效转导。然而，没有产生持久的耐受性，因为在没有免疫抑制的情况下用AAV 8再激发时引发抗AAV 8抗体应答。载体施用途径、载体剂量、AAV血清型或腺病毒载体的伴随施用似乎对NDCD 4抗体和CyA组合缓和对AAV衣壳蛋白的初级体液应答的能力几乎没有影响。NDCD 4和CyA的组合还消除了对转基因产物的体液应答，否则在肌肉内注射AAV 5后必然会发生这种应答，从而导致稳定的转基因表达。这些观察结果可以通过允许重复载体施用和避免转基因产物抗体的产生来显著改善使用rAAV载体治疗慢性疾病的前景。
The ability of transient immunosuppression with a combination of a nondepleting anti-CD4 (NDCD4) antibody and Cyclosporine (CyA) to abrogate immune reactivity to both adeno-associated virus vector (AAV) and its transgene product was evaluated. This combination of immunosuppressants resulted in a 20-fold reduction in the resulting anti-AAV8 antibody titres, to levels in naïve mice, following intravenous administration of 2×1012 AAV8 vector particles/kg to immunocompetent mice. This allowed efficient transduction upon secondary challenge with vector pseudotyped with the same capsid. Persistent tolerance did not result, however, as an anti-AAV8 antibody response was elicited upon rechallenge with AAV8 without immunosuppression. The route of vector administration, vector dose, AAV serotype or the concomitant administration of adenoviral vector appeared to have little impact on the ability of the NDCD4 antibody and CyA combination to moderate the primary humoral response to AAV capsid proteins. The combination of NDCD4 and CyA also abrogated the humoral response to the transgene product, that otherwise invariably would occur, following intramuscular injection of AAV5, leading to stable transgene expression. These observations could significantly improve the prospects of using rAAV vectors for chronic disorders by allowing for repeated vector administration and avoiding the development of antibodies to the transgene product.
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影响因子：
3.1
作者：
Davidoff, AM;Ng, CYC;Nathwani, AC
通讯作者：
Nathwani, AC
影响因子：
5.4
作者：
Chirmule, N;Xiao, WD;Wilson, JM
通讯作者：
Wilson, JM
影响因子：
12.4
作者：
Fields, PA;Arruda, VR;High, KA
通讯作者：
High, KA
DOI：
10.1073/pnas.0508685103
发表时间：
2006-03-21
影响因子：
11.1
作者：
Dobrzynski, E;Fitzgerald, JC;Herzog, RW
通讯作者：
Herzog, RW
影响因子：
4.2
作者：
Ali, RR;Reichel, MB;Thrasher, AJ
通讯作者：
Thrasher, AJ