Blocking KV1.3 Channels Inhibits Th2 Lymphocyte Function and Treats a Rat Model of Asthma

Koshy, Shyny; Huq, Redwan; Tanner, Mark R.; Atik, Mustafa A.; Porter, Paul B.; Khan, Fahad; Pennington, Michael W.; Hanania, Nicola A.; Corry, David B.; Beeton, Christine

doi:10.1074/jbc.m113.517037

Cited by 63 publications

(63 citation statements)

References 52 publications

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“…More recently, K V 1.3 high CCR7 − T EM cells have also been reported in the induced sputum of patients with asthma and in the lungs of rats with asthma. ShK-186 administration reduced IL-4 and IL-5 levels in the lavage fluid, lung infiltration, and airway hyperresponsiveness in the rat asthma model, suggesting that the K V 1.3 blocker also targets Th2-type T EM cells (372). Based on all this positive animal data, Kineta Inc. completed Phase 1a and 1b studies with ShK-186 in 2014 with no major safety findings and is currently planning to start enrolling patients for trials in psoriatic arthritis and psoriasis later in 2014.…”

Section: Ion Channels As Drug Targets For Immunotherapymentioning

confidence: 99%

Ion Channels in Innate and Adaptive Immunity

Feske¹,

Wulff

Skolnik

2015

Annu. Rev. Immunol.

597

616

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Ion channels and transporters mediate the transport of charged ions across hydrophobic lipid membranes. In immune cells, divalent cations such as calcium, magnesium, and zinc have important roles as second messengers to regulate intracellular signaling pathways. By contrast, monovalent cations such as sodium and potassium mainly regulate the membrane potential, which indirectly controls the influx of calcium and immune cell signaling. Studies investigating human patients with mutations in ion channels and transporters, analysis of gene-targeted mice, or pharmacological experiments with ion channel inhibitors have revealed important roles of ionic signals in lymphocyte development and in innate and adaptive immune responses. We here review the mechanisms underlying the function of ion channels and transporters in lymphocytes and innate immune cells and discuss their roles in lymphocyte development, adaptive and innate immune responses, and autoimmunity, as well as recent efforts to develop pharmacological inhibitors of ion channels for immunomodulatory therapy.

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Section: Ion Channels As Drug Targets For Immunotherapymentioning

confidence: 99%

Ion Channels in Innate and Adaptive Immunity

Feske¹,

Wulff

Skolnik

2015

Annu. Rev. Immunol.

597

616

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“…In respiratory diseases, such as asthma and lung carcinoma, verapamil, which also totally and almost irreversibly inhibited the Kv1.3-channel currents in our most recent patch-clamp study [59] ( Table 2), has actually been shown to be useful in the prophylaxis and treatment of the diseases [155][156][157][158]. These findings strongly suggested the usefulness of using commonly used drugs that inhibit the lymphocyte Kv1.3 in the treatment of chronic or acute respiratory diseases as well, in which the over-activation of the channels is responsible for the pathogenesis [93,96,123]. On the other hand, the highly selective inhibitors of the Kv1.3-channels [106,139], which were originally synthesized from venom, scorpion, or sea anemone peptide toxins [159][160][161][162], are likely to cause serious neuromuscular side effects, including epileptic seizures or enteric twitches [163,164].…”

Section: Calcium Channel Blockers Statins and Nsaids As Potent Kv1mentioning

confidence: 79%

“…Among various types of inflammatory leukocytes that infiltrate into the inflamed airways of asthma patients, T lymphocytes play important roles in the pathogenesis of the disease [7,35,36], since the cytokines they produce maintain the activity of the other inflammatory cells [37,38]. Recently, isolating T lymphocytes from the airways or peripheral blood of patients with asthma, Koshy et al demonstrated the increased expression of Kv1.3-channels in these cells [93]. Using a rat model of asthma, they further demonstrated that the administration of ShK-186, a selective inhibitor of the channel, suppressed the proliferation of lymphocytes and their cytokine production and thus actually reduced the airway hyperresponsiveness (Table 1).…”

Section: In Respiratory Diseasesmentioning

confidence: 99%

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Usefulness of targeting lymphocyte Kv1.3-channels in the treatment of respiratory diseases

2015

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T lymphocytes predominantly express delayed rectifier K(+)-channels (Kv1.3) in their plasma membranes. Patch-clamp studies revealed that the channels play crucial roles in facilitating the calcium influx necessary to trigger lymphocyte activation and proliferation. Using selective channel inhibitors in experimental animal models, in vivo studies further revealed the clinically relevant relationship between the channel expression and the development of chronic respiratory diseases, in which chronic inflammation or the overstimulation of cellular immunity in the airways is responsible for the pathogenesis. In chronic respiratory diseases, such as chronic obstructive pulmonary disease, asthma, diffuse panbronchiolitis and cystic fibrosis, in addition to the supportive management for the symptoms, the anti-inflammatory effects of macrolide antibiotics were shown to be effective against the over-activation or proliferation of T lymphocytes. Recently, we provided physiological and pharmacological evidence that macrolide antibiotics, together with calcium channel blockers, HMG-CoA reductase inhibitors, and nonsteroidal anti-inflammatory drugs, effectively suppress the Kv1.3-channel currents in lymphocytes, and thus exert anti-inflammatory or immunomodulatory effects. In this review article, based on the findings obtained from recent in vivo and in vitro studies, we address the novel therapeutic implications of targeting the lymphocyte Kv1.3-channels for the treatment of chronic or acute respiratory diseases.

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“…Therefore, targeting these channels, previous studies revealed the therapeutic usefulness of the channel inhibitors or the openers in the treatment of COPD [19]. Recently, isolating T-lymphocytes from the airways or peripheral blood of patients with asthma, Koshy et al demonstrated the increased expression or activity of Kv1.3-channels in these cells [20]. Using a rat model of asthma, they further demonstrated that the administration of ShK-186, a selective inhibitor of the channel, suppressed the proliferation of lymphocytes and their cytokine production, and thus actually reduced the airway hyper-responsiveness.…”

Section: Involvement Of Lymphocyte Kv13-channels In Copdmentioning

confidence: 99%

Lymphocyte Kv1.3-channels in the pathogenesis of chronic obstructive pulmonary disease: novel therapeutic implications of targeting the channels by commonly used drugs

Kazama

Tamada

2016

Allergy Asthma Clin Immunol

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In patients with chronic obstructive pulmonary disease (COPD), over-activated T-lymphocytes produce pro-inflammatory cytokines and proliferate in situ in the lower airways and pulmonary parenchyma, contributing substantially to the pathogenesis of the disease. Despite our understanding of the molecular mechanisms by which lymphocytes are activated, we know little about the physiological mechanisms. T-lymphocytes predominantly express delayed rectifier K+-channels (Kv1.3) in their plasma membranes and these channels play crucial roles in inducing the lymphocyte activation and proliferation. In the pathogenesis of chronic inflammatory diseases, such as chronic kidney disease (CKD) or inflammatory bowel disease (IBD), these channels, which are overexpressed in proliferating lymphocytes within the inflamed organs, are responsible for the progression of the diseases. Since the over-activation of cellular immunity is also mainly involved in the pathogenesis of COPD, this disease could share similar pathophysiological features as those of CKD or IBD. From a literature review including ours, it is highly likely that the Kv1.3-channels are overexpressed or over-activated in T-lymphocytes isolated from patients with COPD, and that the overexpression of the channels would contribute to the development or progression of COPD. The involvement of the channels leads to novel therapeutic implications of potentially useful Kv1.3-channel inhibitors, such as calcium channel blockers, macrolide antibiotics, HMG-CoA reductase inhibitors and nonsteroidal anti-inflammatory drugs, in the treatment of COPD.

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Blocking KV1.3 Channels Inhibits Th2 Lymphocyte Function and Treats a Rat Model of Asthma

Cited by 63 publications

References 52 publications

Ion Channels in Innate and Adaptive Immunity

Ion Channels in Innate and Adaptive Immunity

Usefulness of targeting lymphocyte Kv1.3-channels in the treatment of respiratory diseases

Lymphocyte Kv1.3-channels in the pathogenesis of chronic obstructive pulmonary disease: novel therapeutic implications of targeting the channels by commonly used drugs

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