TRIM21 mediates antibody inhibition of adenovirus-based gene delivery and vaccination.
TRIM21 mediates antibody inhibition of adenovirus-based gene delivery and vaccination.
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DOI：
10.1073/pnas.1806314115
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发表时间：
2018-10-09
影响因子：
11.1
通讯作者：
James LC
中科院分区：
文献类型：
--
作者：
Bottermann M;Foss S;van Tienen LM;Vaysburd M;Cruickshank J;O'Connell K;Clark J;Mayes K;Higginson K;Hirst JC;McAdam MB;Slodkowicz G;Hutchinson E;Kozik P;Andersen JT;James LC
基于病毒的传递载体在治疗人类疾病方面具有巨大的潜力。作为基因治疗的一部分，腺病毒载体在运送正确的基因以及治疗癌症和传染病的疫苗表位方面被证明是高效的。它们广泛使用的一个主要障碍是抗体能有效地中和它们，将治疗限制在幼稚的患者身上。抗体如何阻断基于腺病毒的转导长期以来一直是一个谜，因为即使它们阻止转基因表达，它们也不能阻止转基因进入靶组织。在这里，我们展示了胞浆抗体受体TRIM21负责截止腺病毒基因治疗和疫苗载体并中和它们。TRIM21的KO基因或阻止相互作用的单一抗体突变足以恢复转基因表达。腺病毒作为基因治疗载体具有巨大的潜力，但原有的免疫限制了它的广泛应用。这种免疫阻断的原因尚不清楚，因为抗体可以有效地抑制转基因表达，而不会阻碍基因转移到靶细胞。在这里，我们表明抗体预防体内的腺病毒基因传递是通过胞浆抗体受体TRIM21介导的。TRIM21的遗传KO或单个抗体点突变足以将转基因表达恢复到近乎天真的免疫水平。TRIM21还负责阻断疫苗载体诱导的细胞毒性T细胞，防止对后续流感感染和移植瘤的保护性反应。此外，腺病毒预先存在的免疫可以在静脉注射时导致增强的免疫反应。对病媒的管理。对载体转导组织的转录分析表明，TRIM21负责数百个免疫基因的特异性上调，其中大多数是内在或先天反应的组成部分。综上所述，这些数据定义了腺病毒基因治疗的免疫前阻断的主要机制，并证明了TRIM21有效地阻断了体内的基因传递，同时诱导了免疫转录的快速程序。
Viral-based delivery vectors have huge potential in the treatment of human disease. Adenoviral vectors specifically have proven highly efficacious in delivering corrected genes, as part of gene therapy, and vaccine epitopes for treating cancer and infectious disease. A principal obstacle to their widespread use is that antibodies potently neutralize them, limiting treatment to naïve patients. How antibodies block adenovirus-based transduction has long remained a mystery because, even though they prevent transgene expression, they do not prevent transgene delivery into target tissue. Here we show that the cytosolic antibody receptor TRIM21 is responsible for intercepting adenoviral gene therapy and vaccine vectors and neutralizing them. Gene KO of TRIM21 or a single-antibody mutation that prevents interaction is sufficient to restore transgene expression. 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-naïve 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.
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影响因子：
5.4
作者：
McCoy, Kimberly;Tatsis, Nia;Ertl, Hildegund C. J.
通讯作者：
Ertl, Hildegund C. J.
影响因子：
5.4
作者：
Bradley, Ritu R.;Maxfield, Lori F.;Barouch, Dan H.
通讯作者：
Barouch, Dan H.
影响因子：
3.7
作者：
Pine, Samuel O.;Kublin, James G.;McElrath, M. Juliana
通讯作者：
McElrath, M. Juliana
DOI：
10.1073/pnas.1507534112
发表时间：
2015-08-11
影响因子：
11.1
作者：
Fletcher, Adam J.;Mallery, Donna L.;James, Leo C.
通讯作者：
James, Leo C.
DOI：
10.1128/cdli.11.2.351-357.2004
发表时间：
2004-03-01
期刊：
CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY
影响因子：
--
作者：
Nwanegbo, E;Vardas, E;Gambotto, A
通讯作者：
Gambotto, A