Immunological thresholds in neurological gene therapy: highly efficient elimination of transduced cells might be related to the specific formation of immunological synapses between T cells and virus-infected brain cells
Immunological thresholds in neurological gene therapy: highly efficient elimination of transduced cells might be related to the specific formation of immunological synapses between T cells and virus-infected brain cells
复制标题
DOI：
10.1017/s1740925x07000579
复制
发表时间：
2006-01-01
影响因子：
--
通讯作者：
Lowenstein, Pedro R.
中科院分区：
文献类型：
--
作者：
Barcia, Carlos;Gerdes, Christian;Lowenstein, Pedro R.
第一代腺病毒可以用强大的启动子工程化以驱动治疗性转基因的表达。使用第一代腺病毒载体的多形性胶质母细胞瘤的许多临床试验已经进行或正在进行中，包括正在欧洲和以色列进行的III期多中心试验（方舟治疗公司）。尽管在脑中不存在抗腺病毒免疫应答表达的情况下持续6 - 18个月，但腺病毒的全身感染诱导免疫应答，所述免疫应答显著抑制来自第一代腺病毒载体的治疗性转基因表达，因此可能损害治疗功效。在这里，我们展示了产生足够强的免疫应答以消除CNS转基因表达的剂量的免疫阈值的证据。对于从脑中消除转基因表达的全身免疫，需要使用>= 1 × 10（7）感染单位（iu）的腺病毒作为免疫原。此外，这种免疫应答消除了60天前注射到纹状体中的1 × 10（7）-1 × 10（3）iu载体的> 90%的转基因表达。重要的是，转基因表达的消除与驱动转基因表达的启动子的性质无关，并且伴随着CD8（+）T细胞和巨噬细胞的脑浸润。总之，一旦超过全身免疫的阈值（即1 × 10（7）in），免疫应答消除转基因表达> 90%，即使是从接受低至1000 IU腺病毒载体的大脑中，与驱动表达的启动子类型无关。
First-generation adenovirus can be engineered with powerful promoters to drive expression of therapeutic transgenes. Numerous clinical trials for glioblastoma multiforme using first generation adenoviral vectors have either been performed or are ongoing, including an ongoing, Phase III, multicenter trial in Europe and Israel (Ark Therapeutics, Inc.). Although in the absence of anti-adenovirus immune responses expression in the brain lasts 6-18 months, systemic infection with adenovirus induces immune responses that inhibit dramatically therapeutic transgene expression from first generation adenoviral vectors, thus, potentially compromising therapeutic efficacy. Here, we show evidence of an immunization threshold for the dose that generates an immune response strong enough to eliminate transgene expression from the CNS. For the systemic immunization to eliminate transgene expression from the brain, >= 1 x 10(7) infectious units (iu) of adenovirus need to be used as immunogen. Furthermore, this immune response eliminates > 90% of transgene expression from 1 x 10(7)-1 x 10(3), iu of vector injected into the striatum 60 days earlier. Importantly, elimination of transgene expression is independent of the nature of the promoter that drives transgene expression and is accompanied by brain infiltration of CD8(+) T cells and macrophages. In conclusion, once the threshold for systemic immunization (i.e. 1 x 10(7) in) is crossed, the immune response eliminates transgene expression by > 90% even from brains that receive as little as 1000 iu of adenoviral vectors, independently of the type of promoter that drives expression.