Background/Purpose: Lymphocyte activation depends upon a calcium signaling cascade that is regulated by voltage-gated potassium channels. Effector memory T cells (T_EM), which are implicated in the immunopathogenesis of a panel of autoimmune diseases, dramatically upregulate the potassium channel Kv1.3, and become dependent on it for cytokine expression and proliferation. Dalazatide is a potent peptide inhibitor of the Kv1.3 channel that has shown potential efficacy in a Phase 1b plaque psoriasis trial. That inflammatory cytokine producing T_EM cells have been implicated in in the pathogenesis of lupus nephritis suggests that targeting Kv1.3 may be a successful strategy in lupus nephritis as well.

Methods: Urinary cells were isolated from patients with systemic lupus erythematosus (SLE). Immunofluorescence was performed to quantify and characterize cells expressing Kv1.3. Peripheral blood T lymphocyte subsets were assayed ex vivo for Kv1.3 expression by flow cytometry. The effect of dalazatide on phorbol myristate acetate (PMA)/ionomycin-induced inflammatory cytokine expression by T_EMcells was evaluated by intracellular cytokine staining.

Results:  In the urine, cells expressing Kv1.3 were found in every subject studied. Kv1.3 expression was detected on CD3+ lymphocytes in 13 of 13 samples studied (mean of 52%,range 10-100%). In 4 of 6 samples, Kv1.3 was detected on CD20+ B lymphocytes (mean 35%, range 0-100%), and CD14+ monocytes/macrophages (mean 50%, range 0-100%).

In the blood, Kv1.3 expression by CD8⁺ T_EM cells was significantly higher in patients with active lupus nephritis when compared to patients with inactive SLE or healthy controls. Dalazatide inhibited IFN-g, IL-17 and TNF-a production by both CD4⁺ and CD8⁺ T_EM cells from SLE patients in a dose-dependent manner. Higher levels of dalazatide-mediated inhibition were observed in IFN-g and TNF-a-expressing CD4⁺ T_EMcells from patients with active SLE when compared to samples from SLE patients with inactive disease.

Conclusion:  Kv1.3 is detectable on urinary B lymphocytes, T lymphocytes, and macrophage, implying that inflammatory cells in the kidney may be targeted by this channel. Peripheral blood cell expression and functional data suggest that SLE T cells are more susceptible to inhibition by dalazatide than healthy T cells.