Background T cell activation depends upon a calcium signalling cascade that is regulated by voltage-gated potassium channels. Effector memory T cells (TEM), which are implicated in the immunopathogenesis of autoimmune diseases, express relatively high levels of the potassium channel Kv1.3. Dalazatide is a potent peptide inhibitor of the Kv1.3 channel that has recently shown safety and efficacy in a Phase 1 b plaque psoriasis trial. Evidence suggests that inflammatory cytokine producing TEM cells might be involved in the immunopathology of lupus nephritis. The objective of this study is to provide proof-of-principle ex vivo data for therapeutically targeting chronic T cell activation in systemic lupus erythematosus (SLE).
Materials and methods Peripheral blood mononuclear cells from paediatric and adult SLE patients as well as healthy controls were studied. T lymphocyte subsets were assayed ex vivo for Kv1.3 expression by flow cytometry. The effect of dalazatide on inflammatory cytokine expression by TEM cells activated by thapsigargin/phorbol myristate acetate (PMA) or ionomycin/PMA was evaluated by intracellular cytokine staining.
Results Kv1.3 expression by CD8+ TEM cells was significantly higher in patients with active lupus nephritis when compared to patients with inactive SLE or healthy controls. Dalazatide inhibited IFN-γ, IL-17 and TNF-α production by both CD4+ and CD8+ TEM cells from SLE patients in a dose-dependent manner. Dalazatide-mediated inhibition was more significant in IFN-γ and TNF-α-expressing CD4+ TEM cells from patients with active SLE compared to cells from patients with inactive disease.
Conclusions Ex vivo studies suggest that dalazatide inhibition of Kv1.3 on TEM may be an effective strategy for treating SLE. In addition, Kv1.3 expression may be a useful biomarker of SLE disease activity.
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