Allergic asthma is a chronic inflammatory disease of the airways and the lung parenchyma associated with airway hyperresponsiveness and mucus hypersecretion. Its incidence has dramatically risen in the past decades and its prevalence is estimated at 5% of the population, asthma is therefore one of the most common chronic diseases worldwide. New therapeutic targets for asthma would therefore have tremendous benefits for public health. CCR7- effector memory conventional T (cTEM) lymphocytes play a major role in autoimmune diseases and in asthma. The role of invariant natural killer T (iNKT) cells in asthma however remains largely unclear. cT lymphocytes express two types of potassium channels, Kv1.3 and KCa3.1. We have found that disease-relevant CCR7- cTEM cells from patients with autoimmune diseases up-regulate the Kv1.3 channel upon activation while disease-irrelevant CCR7+ naive and central memory cT cells from the same patients up-regulate the KCa3.1 channel. We have generated selective blockers of Kv1.3 channels and have shown that these blockers preferentially inhibit proliferation, cytokine production, and motility of CCR7- TEM cells in vitro. More importantly, we have demonstrated the efficacy of Kv1.3 channel blockers in preventing and treating animal models of multiple sclerosis, rheumatoid arthritis, and type-1 diabetes without inducing generalized immunosuppression. Our preliminary data show that iNKT cells express both Kv1.3 and KCa3.1 channels but that expression levels vary between different iNKT cell subsets. Interestingly, T cells in the induced-sputum of patients with asthma up-regulate Kv1.3 channels upon activation. We therefore hypothesize that selective Kv1.3 channel blockers will inhibit lung-infiltrating cT and iNKT cells from patients with asthma and will be effective in preventing and treating an animal model of asthma. In this proposal we will combine studies on samples from patients with asthma and from healthy controls with experiments in an animal model of asthma to establish the intellectual framework for the development of Kv1.3 channel blockers as a therapeutic for asthma.
In Aim 1 we will identify the potassium channel phenotype of iNKT cell subsets isolated from human blood and of cT and iNKT cells isolated from the induced sputum of asthmatic patients and of healthy volunteers.
In Aim 2 we will define the roles of Kv1.3 and KCa3.1 channels in human iNKT cell subsets.
In Aim 3 we will determine whether selective blockers of Kv1.3 and KCa3.1 channels prevent and treat two different animal models of asthma.
Allergic asthma is a chronic inflammatory disease of the airways that affects 5% of the population with an increasing incidence and frequency of complications. Our goal is to define potassium channels on lung-infiltrating T lymphocytes as new targets for the treatment for asthma. Such new therapeutic targets would have tremendous benefits for public health.
