Targeting Delivery Of TNF-alpha Antisense Oligonucleotide In The Treatment Of Pulmonary Inflammation

Background:Anti-tumor necrosis factor a therapeutics has represented the potential to alleviate allergic inflammation. However, in the previous trials, systemic administration of anti-tumor necrosis factor a agents was frequently accompanied with many aspects of adverse effects, such as infections, immunogenicity, malignancies and so on. Efforts are made in this study to evaluate whether or not local administration of tumor necrosis factor a antisense oligonucleotide would inhibit allergic airway inflammation and influence on systemic immune responses in the OVA-induced asthmatic murine model.Methods:The treatment effects of tumor necrosis factor a antisense oligonucleotide-treated mice, as well as the alternative proportion of regulatory T cells and TH2cells, were examined and compared with the untreated.Results:Local administration of tumor necrosis factor a antisense oligonucleotide resulted in significantly inhibited tumor necrosis factor a expression, remarkably decreased inflammatory cell infiltration and dramatically reduced mucus hypersecretion. These treatment effects were associated with the induced CD4+CD25+Foxp3+regulatory T cells, the reduced TH2cells and the generally decreased TH2-type cytokines expression in BALF. Systemic immunosuppression was not triggered by local antisense oligonucleotide administration as the proportion of CD4+CD25+Foxp3+regulatory T cells in blood, thymus or spleen was not affected. The attenuated4-1BBL expression was likely involved in the alternative proportion of T cells.Conclusion:These findings demonstrate that local administration of tumor necrosis factor a antisense oligonucleotide contributes to anti-inflammatory action via the enhancement of regulatory T cells-mediated immune tolerance, which is accompanied with no systemic immunosupression associated with systemically induced regulatory T cells.