原生免疫感应腺相关病毒载体的内在免疫感应
Di Cao1, Barry J Byrne2, Ype P de Jong3
1Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, Indiana, USA.
Human gene therapy
|June 18, 2024
概括
腺相关病毒 (AAV) 载体触发先天性免疫路径,包括收费类受体9 (TLR9) 和补体激活. 这些反应可能导致过度适应性免疫,使基因治疗应用复杂化.
科学领域:
- 免疫学 免疫学 免疫学
- 基因治疗 基因治疗
- 病毒学 病毒学
背景情况:
- 腺相关病毒 (AAV) 载体对于基因疗法至关重要,但免疫反应阻碍了它们的临床使用.
- 最初,由于动物模型中的轻微反应,对AAV载体的先天免疫识别被低估了.
研究的目的:
- 阐明由腺相关病毒 (AAV) 载体激活的先天免疫通路.
- 了解这些先天性免疫激活如何影响基因治疗环境中的适应性免疫反应.
主要方法:
- 通过收费类受体9 (TLR9) 对AAV基因组的检测进行了研究.
- 研究了血细胞树突细胞 (pDC) 的作用及其信号通路 (例如,TLR9>MyD88,IL-1R1>MyD88).
- 评估了AAV囊体与补充元件和收费类受体2 (TLR2) 的相互作用.
主要成果:
- 通过TLR9对AAV基因组的感知促进炎症和干扰素表达,激活pDCs并导致CD8+T细胞激活.
- pDCs还可以通过IL-1细胞因子,独立于TLR9促进CD8+T细胞的反应.
- AAV载体可以诱导单细胞衍生的DC中的细胞因子表达,增强抗体形成和B细胞激活.
- 高剂量的AAV载体可以触发补体激活,导致人类和非人类灵长类动物的严重毒性.
- 有证据表明,TLR2被AAV体和其他先天核酸受体激活.
结论:
- AAV载体激活多个,可能冗余的,先天免疫路径.
- 这些先天性免疫激活导致过度的适应性免疫反应,对基因疗法构成挑战.
- 了解这些途径对于提高基于AAV的基因疗法的安全性和有效性至关重要.
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