title: Locally instilled tumor necrosis factor-α antisense oligonucleotide inhibits allergic inflammation via the induction of Tregs.
abstract: BACKGROUND
  Anti-tumor necrosis factor (TNF)-α therapeutics has the potential to alleviate allergic inflammation. However, in previous studies, the systemic administration of anti-TNF-α agents was frequently accompanied by many adverse effects, such as infection, immunogenicity and malignancy. Efforts are made in the present study to evaluate whether or not local administration of TNF-α antisense oligonucleotide would inhibit allergic airway inflammation and influence systemic immune responses in an ovalbumin-induced asthmatic murine model.
  
  
  METHODS
  The treatment effects of TNF-α antisense oligonucleotide on mice, as well as the alternative proportion of regulatory T cells and T(H) 2 cells, were examined and compared with untreated mice.
  
  
  RESULTS
  Local administration of TNF-α antisense oligonucleotide resulted in significantly inhibited TNF-α expression, remarkably decreased inflammatory cell infiltration and dramatically reduced mucus hypersecretion. These treatment effects were associated with induced CD4(+) CD25(+) Foxp3(+) regulatory T cells, reduced T(H) 2 cells and generally decreased T(H) 2-type cytokines expression in bronchoalveolar lavage fluid. Systemic immunosuppression was not triggered by local antisense oligonucleotide administration because the proportion of CD4(+) CD25(+) Foxp3(+) regulatory T cells in the blood, thymus or spleen was not affected. Attenuated 4-1BBL expression was likely involved in the alternative proportion of T cells.
  
  
  CONCLUSIONS
  These findings demonstrate that local administration of TNF-α antisense oligonucleotide contributes to anti-inflammatory action via the enhancement of regulatory T cells-mediated immune tolerance, which is not accompanied by systemic immunosuppression associated with systemically-induced regulatory T cells.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Luo
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Pang
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhu
authors.forename: Xing
authors.initials: X
authors.lastname: Cai
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yin
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
authors.forename: Jiangning
authors.initials: J
authors.lastname: Chen
authors.forename: Ke
authors.initials: K
authors.lastname: Zeng
authors.forename: Chenyu
authors.initials: C
authors.lastname: Zhang
authors.forename: Junfeng
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000628:therapy*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D017252:CD3 Complex / Q000096:biosynthesis; D015704:CD4 Antigens / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D007249:Inflammation / Q000628:therapy; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D008168:Lung / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D010047:Ovalbumin; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology
chemical_list: D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D016376:Oligonucleotides, Antisense; D014409:Tumor Necrosis Factor-alpha; D010047:Ovalbumin