Kv1.3 blockers ameliorate allergic contact dermatitis by preferentially suppressing effector memory T cells in a rat model

Abstract

SummaryBackground. The Kv1.3 voltage-gated potassium channel is selectively upregulated upon activation in effector memory T (T EM ) cells in inflamed tissue, and plays an important role in maintenance of T-cell activation. Although Kv1.3 blockers have been shown to ameliorate allergic contact dermatitis (ACD) in a rat model, it remains unknown whether the effect of Kv1.3 blockers on ACD is mediated by suppressing T EM cell function and/or whether naive T-cells or central memory T (T CM ) cells are influenced. Aim. To analyse the detailed mechanism of Kv1.3 blockers in a rat model of ACD. Methods. We examined the effects of a Kv1.3 blocker on inflammation and production of the effector cytokine interferon (IFN)-c in inflamed tissue in rat ACD. Singlecell suspensions were isolated from inflamed rat ears (T EM cells), and regional lymph nodes (naive T/T CM cells), and the effect of Kv1.3 blockers on anti-CD3-stimulated IFN-c production in vitro was measured.Results. The Kv1.3 blocker significantly suppressed ear inflammation and IFN-c production at the protein level in vivo. It also suppressed in vitro IFN-c production from T EM cells from inflamed tissues, but did not suppress the function of naive T/T CM cells from lymph nodes. Conclusions. We found that the Kv1.3 blocker ameliorated ACD by inhibiting T EM cell functions only, thus Kv1.3 blockers could be a potentially selective therapeutic agent for T EM cell-mediated inflammatory skin diseases without producing harmful side-effects.

Alopecia areata: Animal models illuminate autoimmune pathogenesis and novel immunotherapeutic strategies

“…The agent has been approved by the FDA for treatment of psoriatic arthritis and moderate-to-severe psoriasis [104,105] and is currently being considered for clinical trials for AA. The KV1.3 blocker is known to suppress the production of pro-inflammatory cytokine like IFN-γ and IL-2 and T cell proliferation in human effector memory T cells [106,107]. Neither of these agents appears to cause systemic immune suppression, and both reportedly have a favorable toxicity profile in vivo [108,109].…”

Potassium channels Kv1.3 and KCa3.1 cooperatively and compensatorily regulate antigen-specific memory T cell functions

“…Inhibition of Kv1.3 with ShK or its derivatives has shown partial efficacy in preclinical autoimmune disease rat models including experimental autoimmune encephalomyelitis151920, pristane-induced arthritis15, and experimental autoimmune diabetes15, as well as in T-cell-dependent models of delayed-type hypersensitivity (DTH)1521, allergic contact dermatitis2223 and asthma24. Despite the ability of Kv1.3 inhibitors to impede preclinical models of autoimmune disease, it is not clear whether inhibition of Kv1.3 is sufficient to fully inhibit pathological T-cell activation and effector function.…”

Curcumin Nanoparticles Enhance Mycobacterium bovis BCG Vaccine Efficacy by Modulating Host Immune Responses

“…Therefore, a strategy that enhances T CM responses may provide improved vaccine efficacy. K V 1.3 is a potassium channel predominantly expressed on T EM cells and is required for the differentiation of T CM cells into T EM cells (33, 34). Hence, blocking the K V 1.3 channel may amplify CD4 + and CD8 + T CM cells.…”