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- Title
Ischemia/reperfusion injury-mediated down-regulation of adenovirus-mediated gene expression in a rat heart transplantation model is inhibited by co-application of a TNFRp55-Ig chimeric construct.
- Authors
Ritter, T; Schröder, G; Risch, K; Vergopoulos, A; Shean, M K; Kolls, J; Brock, J; Lehmann, M; Volk, H-D
- Abstract
El-deleted adenoviral vectors are efficient vectors for somatic gene therapy. Recently, we have shown that intratracheal application of an adenoviral reporter construct leads to significant reporter gene expression in rat lungs within 24 h. In contrast, reporter gene expression in syngeneic rat heart transplants after adenovirus-mediated gene transfer was delayed. Since the adenovirus cannot replicate, downregulation of the hCMV-IE promoter controlled reporter gene expression in initially infected cells by cytokines, which are released as a result of ischemia/reperfusion injury, might be involved. In order to investigate the role of proinflammatory cytokines, eg TNF-α in affecting hCMV-IE promoter-driven reporter gene expression, transient blockade of TNF-α was achieved by local co-application of an Ad-construct encoding for a soluble TNFRp55-lg chimeric molecule in a syngeneic rat heart transplantation model Co-application of the reporter construct together with the TNFRp55-lg chimeric molecule significantly increased the early reporter gene expression after transplantation. Moreover, infiltration of inflammatory cells (T cells, macrophages, NK cells) and production of TNF-α in the transplant was markedly reduced. Our results indicate that: (1) proinflammatory cytokines are involved in down-regulation of reporter gene expression in ischemia/reperfusion injured tissues; and (2) inhibition of TNF-α might be a useful tool to increase early gene expression in gene therapy protocols, particularly in transplantation.
- Subjects
ISCHEMIA; REPERFUSION injury; ADENOVIRUSES; GENE expression
- Publication
Gene Therapy, 2000, Vol 7, Issue 14, p1238
- ISSN
0969-7128
- Publication type
Article
- DOI
10.1038/sj.gt.3301222