SummaryTolerogenic dendritic cells (tolDC) are a new immunotherapeutic tool for the treatment of rheumatoid arthritis (RA) and other autoimmune disorders. We have established a method to generate stable tolDC by pharmacological modulation of human monocyte-derived DC. These tolDC exert potent pro-tolerogenic actions on CD4 1 T cells. Lack of interleukin (IL)212p70 production is a key immunoregulatory attribute of tolDC but does not explain their action fully. Here we show that tolDC express transforming growth factor (TGF)-b1 at both mRNA and protein levels, and that expression of this immunoregulatory cytokine is significantly higher in tolDC than in mature monocyte-derived DC. By inhibiting TGF-b1 signalling we demonstrate that tolDC regulate CD4 1 T cell responses in a manner that is at least partly dependent upon this cytokine. Crucially, we also show that while there is no significant difference in expression of TGFbRII on CD4 1 T cells from RA patients and healthy controls, RA patient from RA patients can, nonetheless, be regulated efficiently by tolDC in a TGF-b1-dependent manner. This work is important for the design and development of future studies investigating the potential use of tolDC as a novel immunotherapy for the treatment of RA.
Although previous studies have shown that prostaglandins (PGs), leukotrienes (LTs), and other arachidonic acid (AA) metabolites play an important role in the pathogenesis of otitis media with effusion (OME), the exact role of each AA metabolite in OME is still unknown. The purpose of this study was to examine the effect of several individual AA metabolites alone or in combination and AA itself on experimental otitis media in chinchillas. Normal chinchillas were inoculated daily with normal saline, PGE2, LTC4, LTC4 + PGE2, and AA through the superior bullae over 7 days. Animals were followed by otoscopy and tympanometry, samples of middle ear effusion were collected for biochemical assay, and temporal bones were processed for histopathology. The highest number of ears that developed OME was in the group inoculated with PGE2 + LTC4. The degree of inflammatory change was more pronounced in groups injected with LTC4 than any other group. The findings of this study suggest that eicosanoids PGE2, LTC4, and AA alone or in combination inoculated into the middle ear can induce OME.
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