Route of administration determines induction of T-cell-independent humoral responses to adeno-associated virus vectors.
Route of administration determines induction of T-cell-independent humoral responses to adeno-associated virus vectors.
复制标题
给药途径决定了对腺相关病毒载体的 T 细胞依赖性体液反应的诱导。
DOI：
10.1006/mthe.2000.0045
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Wilson,JM
中科院分区：
文献类型：
--
作者：
Xiao,W;Chirmule,N;Schnell,MA;Tazelaar,J;Hughes,JV;Wilson,JM
基于2型腺相关病毒（AAV）的载体显示出治疗慢性疾病的希望，因为转基因表达似乎是稳定的。本研究评估了体液免疫对衣壳蛋白在血管内途径后对肝细胞载体摄取的影响。载体给药途径对小鼠抗载体B细胞反应有定性影响。将载体注入尾静脉导致t细胞依赖（TD） B细胞反应，CD4抗体的消耗完全抑制了这种反应。载体经脾进入门静脉循环产生部分T细胞独立（TI）的B细胞应答，使得基于T细胞抑制的策略在允许载体再给药方面无效。与TD反应相比，TI B细胞反应是短暂的。恒河猴对门静脉内载体产生B细胞记忆反应，根据Ig同种型，这似乎依赖于T细胞。需要AAV载体再给药的基因治疗策略应考虑载体的生物分布及其对B细胞活化的影响。
Vectors based on adeno-associated viruses (AAV) type 2 show promise for treating chronic diseases because transgene expression appears to be stable. This study evaluated the impact of humoral immunity to the capsid proteins on vector uptake by hepatocytes following an intravascular approach. Route of vector administration in mice had a qualitative effect on antivector B cell responses. Administration of vector into the tail vein resulted in T-cell-dependent (TD) B cell responses that were completely inhibited with depleting CD4 antibody. Delivery of vector into the portal circulation via the spleen yielded B cell response that were partially T cell independent (TI) rendering strategies based on T cell inhibition ineffective in allowing vector readministration. The TI B cell response was short lived in comparison to the TD response. Rhesus monkeys produced a B cell memory response to intraportal vector which appeared to be T cell dependent based on Ig isotypes. Gene therapy strategies that require AAV vector readministration should consider vector biodistribution and its impact on B cell activation.