Down‐regulation of the nonspecific and antigen‐specific T cell cytokine response in ankylosing spondylitis during treatment with infliximab

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Abstract
Objective Treatment of active ankylosing spondylitis (AS) with the monoclonal tumor necrosis factor α (TNFα) antibody infliximab is highly clinically effective. This study was undertaken to investigate the precise mechanism of action of anti‐TNFα treatment in AS. Methods Cytokine expression of CD4+ and CD8+ T cells was investigated before and 6 and 12 weeks after the start of treatment in 10 patients treated with infliximab, and before and after 6 weeks of treatment and 6 weeks after placebo was switched to infliximab in 10 patients treated initially with placebo. Peripheral blood mononuclear cells (PBMCs) were stimulated for 6 hours either nonspecifically with phorbol myristate acetate (PMA)/ionomycin or antigen specifically with a pool of 46 overlapping 18‐mer peptides derived from the G1 domain of aggrecan. Cells were stained for T cell surface markers CD4 and CD8 and for the intracellular cytokines interferon‐γ (IFNγ), TNFα, interleukin‐4 (IL‐4), and IL‐10. Positive cells were quantified by flow cytometry. For monocyte‐derived cytokines, PBMCs were stimulated with lipopolysaccharide (LPS) for 18 hours and TNFα and IL‐10 in the supernatant were measured by enzyme‐linked immunosorbent assay. Results Compared with baseline, infliximab treatment induced a significant decrease at 12 weeks in the number of CD4+ and CD8+ T cells that were positive for IFNγ and TNFα upon PMA/ionomycin stimulation (P = 0.005). A significant reduction had already begun to occur at 6 weeks. No change in the percent IFNγ or TNFα positivity among CD4+ and CD8+ subpopulations was observed after 6 weeks in patients treated with placebo. However, when these patients began infliximab treatment after 6 weeks of receiving placebo, there was a similar significant decrease in IFNγ and TNFα production by CD4+ and CD8+ T cells (P < 0.05). Furthermore, infliximab treatment induced a significant reduction in the number of IFNγ+ and TNFα+ CD8+ T cells (P = 0.005 at week 6 and week 12) after antigen‐specific in vitro stimulation with G1‐derived peptides. Between‐group analysis showed that the change in the expression of IFNγ and TNFα in both CD4+ and CD8+ T cells was significantly different between the infliximab and placebo groups (P = 0.001 for all variables). There was no change in the number of IL‐10+ or IL‐4+ T cells during treatment. No significant change in the production of TNFα and IL‐10 upon in vitro stimulation of PBMCs with LPS was detectable during infliximab treatment. Conclusion Infliximab down‐regulates both IFNγ and TNFα secreted by T cells but does not induce a change in cytokines produced by monocytes during 3 months of treatment. This is likely to be a relevant mechanism for the clinical efficacy of this therapy.

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