title: Blocking KV1.3 channels inhibits Th2 lymphocyte function and treats a rat model of asthma.
abstract: Allergic asthma is a chronic inflammatory disease of the airways. Of the different lower airway-infiltrating immune cells that participate in asthma, T lymphocytes that produce Th2 cytokines play important roles in pathogenesis. These T cells are mainly fully differentiated CCR7(-) effector memory T (TEM) cells. Targeting TEM cells without affecting CCR7(+) naïve and central memory (TCM) cells has the potential of treating TEM-mediated diseases, such as asthma, without inducing generalized immunosuppression. The voltage-gated KV1.3 potassium channel is a target for preferential inhibition of TEM cells. Here, we investigated the effects of ShK-186, a selective KV1.3 channel blocker, for the treatment of asthma. A significant proportion of T lymphocytes in the lower airways of subjects with asthma expressed high levels of KV1.3 channels. ShK-186 inhibited the allergen-induced activation of peripheral blood T cells from those subjects. Immunization of F344 rats against ovalbumin followed by intranasal challenges with ovalbumin induced airway hyper-reactivity, which was reduced by the administration of ShK-186. ShK-186 also reduced total immune infiltrates in the bronchoalveolar lavage and number of infiltrating lymphocytes, eosinophils, and neutrophils assessed by differential counts. Rats with the ovalbumin-induced model of asthma had elevated levels of the Th2 cytokines IL-4, IL-5, and IL-13 measured by ELISA in their bronchoalveolar lavage fluids. ShK-186 administration reduced levels of IL-4 and IL-5 and induced an increase in the production of IL-10. Finally, ShK-186 inhibited the proliferation of lung-infiltrating ovalbumin-specific T cells. Our results suggest that KV1.3 channels represent effective targets for the treatment of allergic asthma.
authors.affiliation: From the Department of Molecular Physiology and Biophysics.
authors.forename: Shyny
authors.initials: S
authors.lastname: Koshy
authors.forename: Redwan
authors.initials: R
authors.lastname: Huq
authors.forename: Mark R
authors.initials: MR
authors.lastname: Tanner
authors.forename: Mustafa A
authors.initials: MA
authors.lastname: Atik
authors.forename: Paul C
authors.initials: PC
authors.lastname: Porter
authors.forename: Fatima S
authors.initials: FS
authors.lastname: Khan
authors.forename: Michael W
authors.initials: MW
authors.lastname: Pennington
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Hanania
authors.forename: David B
authors.initials: DB
authors.lastname: Corry
authors.forename: Christine
authors.initials: C
authors.lastname: Beeton
mesh_terms: D000328:Adult; D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D018793:Interleukin-13 / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D015848:Interleukin-5 / Q000276:immunology / Q000378:metabolism; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010047:Ovalbumin / Q000276:immunology; D026902:Potassium Channel Blockers / Q000276:immunology / Q000494:pharmacology; D011506:Proteins / Q000276:immunology / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D055815:Young Adult
chemical_list: D018793:Interleukin-13; D015848:Interleukin-5; D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers; D011506:Proteins; C533637:Shk-186 peptide; D016753:Interleukin-10; D015847:Interleukin-4; D010047:Ovalbumin
keywords: Airway Inflammation; Allergy; Animal Models; Asthma; Cellular Immune Response; KCNA3; KV1.3; Potassium Channels; T Lymphocyte; Therapy