title: Locally instilled tumor necrosis factor α antisense oligonucleotide contributes to inhibition of TH 2-driven pulmonary fibrosis via induced CD4+ CD25+ Foxp3+ regulatory T cells.
abstract: 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.
authors: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
authors: Yi
authors: Y
authors: Luo
authors: Min
authors: M
authors: Wang
authors: Zhonghua
authors: Z
authors: Pang
authors: Fengtao
authors: F
authors: Jiang
authors: Jiangning
authors: J
authors: Chen
authors: Junfeng
authors: J
authors: Zhang
mesh_terms: D053330:4-1BB Ligand / Q000235:genetics / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D015704:CD4 Antigens / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage*; D011658:Pulmonary Fibrosis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry / Q000235:genetics*
chemical_list: D053330:4-1BB Ligand; D000199:Actins; D015704:CD4 Antigens; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D016376:Oligonucleotides, Antisense; D014409:Tumor Necrosis Factor-alpha; C544013:alpha-smooth muscle actin, mouse
keywords: TH2-biased responses; anti-TNF-α therapeutics; antisense oligonucleotide; pulmonary fibrosis; regulatory T cells