Locally instilled tumor necrosis factor-α antisense oligonucleotide inhibits allergic inflammation via the induction of Tregs.

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.