| Summary: | Anti-tumour necrosis factor-a (TNF-a) therapy is an effective treatment for Rheumatoid Arthritis (RA), in part by enhancing immune regulation. It was hypothesised that these immunomodulatory activities were mediated via effects of TNF-a blockade on dendritic cells (DC). Therefore, the effect of this treatment on the survival, phenotype and ability Df DC to modulate T cells was investigated using infliximab and p55 sTNF Receptor-Ig fusion protein (p55 sTNFR-Ig) as TNF-a antagonists. In addition, the phenotype and survival of DC from RA patients pre and during anti-TNF-a therapy were investigated. Monocyte-derived DC (moDC) from healthy donors were stimulated with LPS in the presence of TNF-a antagonists for 48 hours. The survival, maturation, cytokine profile and the T cell skewing capacity of these DC was measured. Both p55 sTNF R-Ig and infliximab resulted in apoptosis of 40 % of the DC during LPS stimulation in part, due to soluble TNF-a blockade. The surviving cells expressed lower levels of CD80, CD83, CD86 and CCR7 and produced more IL-10 upon re-stimulation through CD40. Moreover, DC treated with TNF-a antagonists stimulated T cells poorly and modulated T cells to produce lower levels of IFN-y, and increased IL-10 upon re-stimulation through CD40. Moreover, DC treated with TNF-α antagonists stimulated T cells poorly and modulated T cells to produce lower levels of IFN-γ, and increased IL-10, IL-4, IL-17 and IL-6 upon re-stimulation with anti-CD3/28 beads.MoDC generated from RA patients ex-vivo during in-vivo anti-TNF-a therapy, were less responsive to IPS, shown by a decrease in CD80 and CD86 expression and less able to activate T cell proliferation compared to pre anti-TNF-a therapy.
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