中文摘要：

腺病毒作為基因治療載體擁有巨大應用潛力，但機體預先存在的免疫應答限制了它的廣泛使用。目前尚不清楚造成這一免疫阻礙的具體機制：抗體可強烈抑制轉基因表達，卻不會阻礙載體向靶細胞的基因遞送。本文證實：體內抗體對腺病毒基因遞送的阻斷作用，由胞質抗體受體 TRIM21 介導。敲除 TRIM21 基因，或對抗體進行單位點突變，就足以將轉基因表達恢復至接近未免疫個體的水平。

TRIM21 還會阻礙疫苗載體誘導細胞毒性 T 細胞應答，使機體無法對后續流感病毒感染以及移植腫瘤產生保護性免疫。此外，靜脈注射腺病毒載體時，機體預存免疫還會引發免疫應答增強效應。對載體轉導組織開展轉錄組分析發現，TRIM21 特異性介導數百個免疫基因上調，其中絕大多數屬于固有免疫通路組分。

綜上，本研究闡明了預存免疫阻礙腺病毒基因治療的核心機制；證實 TRIM21 可在體內高效阻斷基因遞送，同時啟動快速的免疫轉錄程序。

英文摘要：

Adenovirus has enormous potential as a gene-therapy vector, but preexisting immunity limits its widespread application. What is responsible for this immune block is unclear because antibodies potently inhibit transgene expression without impeding gene transfer into target cells. Here we show that antibody prevention of adenoviral gene delivery in vivo is mediated by the cytosolic antibody receptor TRIM21. Genetic KO of TRIM21 or a single-antibody point mutation is sufficient to restore transgene expression to near-na?ve immune levels. TRIM21 is also responsible for blocking cytotoxic T cell induction by vaccine vectors, preventing a protective response against subsequent influenza infection and an engrafted tumor. Furthermore, adenoviral preexisting immunity can lead to an augmented immune response upon i.v. administration of the vector. Transcriptomic analysis of vector-transduced tissue reveals that TRIM21 is responsible for the specific up-regulation of hundreds of immune genes, the majority of which are components of the intrinsic or innate response. Together, these data define a major mechanism underlying the preimmune block to adenovirus gene therapy and demonstrate that TRIM21 efficiently blocks gene delivery in vivo while simultaneously inducing a rapid program of immune transcription.

論文信息：

論文題目：TRIM21 mediates antibody inhibition of adenovirus-based gene delivery and vaccination

期刊名稱：PNAS

時間期卷：115 (41) 10440-10445

Doi.org/10.1073/pnas.1806314115

產品信息：

貨號：CP-010-010

規格：10ml+10ml

品牌：Liposoma

產地：荷蘭

名稱：Clodronate Liposomes&Control Liposomes

辦事處：靶點科技

Clodronate Liposomes氯膦酸鹽脂質體清除腺病毒遞送小鼠肝臟巨噬細胞。荷蘭Liposoma巨噬細胞清除劑ClodronateLiposomes見刊于PNAS：TRIM21介導抗體對基于腺病毒的基因遞送和疫苗接種的抑制作用。

Liposoma巨噬細胞清除劑Clodronate Liposomes氯膦酸二鈉脂質體清除巨噬細胞的材料和方法：

In vivo macrophage depletion

Liver Macrophage Depletion.

巨噬細胞清除材料和方法文獻截圖：