Locally instilled tumor necrosis factor α antisense oligonucleotide contributes to inhibition of TH2‐driven pulmonary fibrosis via induced CD4+CD25+Foxp3+ regulatory T cells. (November 2013)

• Record Type: Journal Article
• Authors: Luo, Yi; Wang, Min; Pang, Zhonghua; Jiang, Fengtao; Chen, Jiangning; Zhang, Junfeng
• Is Part Of: Journal of gene medicine. Volume 15:Number 11/12(2013)
• Page Start: 441
• Page End: 452
• Publication Date: 2013-11
• Subjects: Genetic transformation -- Periodicals; Gene Transfer -- Periodicals; Gene Therapy -- Periodicals; 616.042
• DOI: 10.1002/jgm.2750
• Languages: English
• ISSNs: 1099-498X

Abstract

<abstract abstract-type="main"> <title>Abstract</title> <sec id="jgm2750-sec-0001" sec-type="section"> <title>Background</title> <p>Anti‐tumor necrosis factor α therapeutics has the potential to alleviate pulmonary fibrosis. However, the systemic administration of anti‐tumor necrosis factor α agents has brought about contradictory results and frequent adverse effects, such as infections, immunogenicity and malignancies, amongst others. In the present study, we attempted the local administration of tumor necrosis factor α antisense oligonucleotide and evaluated the treatment effects on pulmonary fibrosis in a bleomycin‐induced pulmonary fibrosis mouse model.</p> </sec> <sec id="jgm2750-sec-0002" sec-type="section"> <title>Methods</title> <p>Flow cytometry for regulatory T cells, reverse transcriptase‐polymerase chain reaction for crucial gene expression, western blotting for crucial protein products, immunofluorescent analysis for T<sub>H</sub>2 cells and myofibroblasts, as well as histology analysis for pathological examination, were used.</p> </sec> <sec id="jgm2750-sec-0003" sec-type="section"> <title>Results</title> <p>By local administration of tumor necrosis factor α antisense oligonucleotide, we investigated whether tumor necrosis factor α expression in epithelial cells was significantly inhibited and extracellular matrix overexpression was dramatically reduced. These treatment effects were associated with induced regulatory T cells, reduced T<sub>H</sub>2 cells and generally decreased T<sub>H</sub>2‐type cytokine expression. Systemic immunosuppression was not triggered by local antisense oligonucleotide administration because the proportion of regulatory T cells in the blood, thymus or spleen was not affected.</p> </sec> <sec id="jgm2750-sec-0004" sec-type="section"> <title>Conclusions</title> <p>These findings demonstrate that local administration of tumor necrosis factor α antisense oligonucleotide contributes to anti‐fibrotic action via a sustained up‐regulated level of regulatory T cells, which inhibits T<sub>H</sub>2‐biased responses, pro‐fibrotic mediator production and extracellular matrix deposition, with no systemic immunosupression associated with systemically induced regulatory T cells. Copyright © 2013 John Wiley & Sons, Ltd.</p> </sec> </abstract>