Introduction Dendritic cells (DC) play a key role in discriminating between commensal microorganisms and potentially harmful pathogens. Expression of surface markers and cytokine production by DC at the time of antigen presentation control T-cell differentiation, cytokine profile & homing properties imprinted on stimulated T-cells. This process defines the type of immune response that occurs and its anatomical location. In CD, dysregulation of the immune response to gut microbiota and aberrant immune cell trafficking play a central role in disease pathogenesis. Infliximab (IFX) is an effective treatment for CD, but its mechanism of action is unclear. In this study, we investigated the effect of IFX pre-treated blood-enriched DC, isolated from patients with active CD and healthy controls (HC), on human T-cell proliferation, phenotype&cytokine production
Methods Low density cells (LDC), enriched for DC, were obtained following Ficoll and Nycoprep gradient separation of fresh blood from patients with active ileocolonic CD (CDAI > 220) and HC. LDC were cultured (0.5x106cells/ml) with IFX (1.10μg&100μg/ml&basal) for 24hr. T-cells were enriched from allogeneic HC blood and labelled with CFSE. LDC were added to T-cells in complete medium (400,000cells/ml) at basal,1.2&3% concentrations and incubated for 5days. Following incubation, T-cell proliferation, expression of β7&CLA surface homing markers and cytokine content of T-cells (TNFα, TGFβ, IFNγ, IL-10.15.17) was quantified by flow cytometry on stimulated T-cells. Unparied t-test and one-way ANOVA statistical analyses were applied
Results In basal conditions, LDC from HC & CD patients did not differ in their stimulatory capacity for allogeneic T-cells or in the cytokine profile acquired by T-cells. However, T-cells stimulated by LDC from CD patients decreased β7 intensity ratio. Following culture with IFX, LDC decreased their stimulatory capacity in a dose-dependent, stepwise fashion in both HC and CD. Culture with IFX did not have any effect on the acquired homing profile of stimulated T-cells, although these T-cells had a trend (not statistically significant) towards lower TNFα and higher IL-17 production
Conclusion The marked reduction in the ability of LDC to stimulate T-cells following culture with IFX represents one plausible explanation for the efficacy of anti TNF-alpha therapies in the treatment of CD. This effect was dose-dependent (within our range of test concentrations) suggesting that higher doses of IFX further reduce T-cell stimulation and may provide one explanation of the clinical benefits of dose escalation in refractory CD
Disclosure of Interest None Declared.
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