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Locally instilled tumor necrosis factor α antisense oligonucleotide contributes to inhibition of T H 2‐driven pulmonary fibrosis via induced CD4 + CD25 + Foxp3 + regulatory T cells
Author(s) -
Luo Yi,
Wang Min,
Pang Zhonghua,
Jiang Fengtao,
Chen Jiangning,
Zhang Junfeng
Publication year - 2013
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.2750
Subject(s) - tumor necrosis factor alpha , cancer research , pulmonary fibrosis , fibrosis , il 2 receptor , microbiology and biotechnology , biology , foxp3 , cytokine , immunology , medicine , pathology , t cell , immune system
Background 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. Methods 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 H 2 cells and myofibroblasts, as well as histology analysis for pathological examination, were used. Results 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 H 2 cells and generally decreased T H 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. Conclusions 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 H 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.