Adenoviral-mediated transduction of human pancreatic islets:: Importance of adenoviral genome for cell viability and association with a deficient antiviral response

被引:22
作者
Barbu, AR
Akusjärvi, G
Welsh, N
机构
[1] Univ Uppsala, Ctr Biomed, Dept Med Cell Biol, S-75123 Uppsala, Sweden
[2] Univ Uppsala, Dept Med Biochem & Microbiol, S-75123 Uppsala, Sweden
关键词
D O I
10.1210/en.2004-1667
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
As adenoviral vectors are extensively used for genetic manipulation of insulin-producing cells in vitro, there is an increasing need to evaluate their effects on the function, morphology, and viability of transduced pancreatic islets. In the present study we observed that specific adenoviral genotypes, carrying E4 and E1/E3 deletions, correlate with differential induction of necrosis in pancreatic islet cells. In particular, the adenovirus death protein encoded from the E3 region of the adenoviral genome was able to modulate the changes induced in the morphology and viability of the transduced cells. We also propose a putative role for the transcriptional regulator pIX. Although human islet cells showed an increased resistance in terms of viral concentrations required for the induction of cell toxicity, our results showed that they were unable to build up an efficient antiviral response after transduction and that their survival was dependent on the exogenous addition of alpha-interferon. An intact and fully functional beta-cell is crucial for the successful application of gene therapy approaches in type 1 diabetes, and therefore, the implications of our findings need to be considered when designing vectors for gene transfer into pancreatic beta-cells.
引用
收藏
页码:2406 / 2414
页数:9
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