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: Yi Luo, Zhonghua Pang, Qian Zhu, Xing Cai, Yuan Yin, Min Wang, Jie Zhu, Jiangning Chen, Ke Zeng, Chenyu Zhang, Junfeng Zhang
• Journal: The journal of gene medicine (J Gene Med) Vol. 14 Issue 6 Pg. 374-83 (Jun 2012) ISSN: 1521-2254 [Electronic] England
• PMID: 22576979 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 John Wiley & Sons, Ltd.

Chemical References

• CD3 Complex
• CD4 Antigens
• CD8 Antigens
• Forkhead Transcription Factors
• Foxp3 protein, mouse
• Interleukin-2 Receptor alpha Subunit
• Oligonucleotides, Antisense
• Tumor Necrosis Factor-alpha
• Ovalbumin

Topics

• Animals
• Asthma (chemically induced, therapy)
• Bronchoalveolar Lavage Fluid (chemistry, immunology)
• CD3 Complex (biosynthesis)
• CD4 Antigens (biosynthesis)
• CD8 Antigens (biosynthesis)
• Female
• Forkhead Transcription Factors (biosynthesis)
• Inflammation (therapy)
• Interleukin-2 Receptor alpha Subunit (biosynthesis)
• Lung (immunology, metabolism)
• Mice
• Mice, Inbred BALB C
• Oligonucleotides, Antisense (administration & dosage, metabolism, pharmacology)
• Ovalbumin
• T-Lymphocytes, Regulatory (immunology)
• Th2 Cells (immunology)
• Tumor Necrosis Factor-alpha (biosynthesis, genetics, immunology)