Background Psoriasis is a chronic inflammatory skin disease characterized by hyperproliferation and altered differentiation of keratinocytes in reply to cytokines such as interferon (IFN)-γ and tumour necrosis factor (TNF)-α, provided by infiltrating CD4+ and CD8+ T cells and natural killer cells. Infliximab is a chimeric monoclonal antibody that neutralizes both soluble and membrane-bound TNF-α, and that may give a long-term disease remission.
Objectives To determine the in vitro effects of infliximab on CD4+ and CD8+ T cells derived from lesional skin, and on dendritic cells (DCs).
Methods Psoriatic T-cell lines were isolated from lesional skin of four patients with psoriasis and assayed for their proliferation, cytokine release and susceptibility to apoptotic stimuli in the presence of graded (1–100 μg mL−1) concentrations of infliximab. DCs were differentiated in the presence of infliximab from peripheral blood monocytes. Phenotype was assessed by fluorescence-activated cell sorting and antigen-presenting capacity in functional assays.
Results In vitro activation of psoriatic as well as antigen (nickel)-specific skin-homing T cells was strongly and dose-dependently impaired by infliximab, in terms both of proliferation and of IFN-γ release. Despite the significant reduction of IFN-γ secretion, infliximab only marginally affected the release of interleukin (IL)-10 by skin T cells, thus determining a reduction of the IFN-γ/IL-10 ratio at the site of inflammation. The effects were maximal when T-cell activation occurred in the absence of costimulation, or when T cells were activated by immature compared with mature DCs. In addition, skin-homing CD8+ T cells were more prominently affected by infliximab compared with CD4+ T lymphocytes, both in terms of inhibition of activation and in their susceptibility to apoptosis. Finally, infliximab directly affected the differentiation of monocyte-derived DCs, by inhibiting the expression of CD1a and CD86, and strongly impaired the antigen-presenting capacity of immature and, to a lesser extent, mature DCs.
Conclusions Infliximab directly affects psoriatic T cells and impairs the antigen-presenting capacity of DCs. These effects may help to explain the long-term disease remission obtained with the drug.