Potassium (K+) channels expressed in immune cells have gained attention recently as promising targets of immunotherapy for multiple sclerosis (MS). We have previously shown that naove and central memory T cells (TCM) predominantly use the calcium-dependent potassium channel KCa3.1 during acute activation, whereas effector memory T cells (TEM), which are likely to be the pathogenic population in MS, utilize the voltage-gated potassium channel Kv1.3. Further, only TEM were inhibited by Kv1.3- specific pharmacological blockade, as naove T cells and TCM bypassed this inhibition via up regulation KCa3.1, indicating the potential for selectivity of this approach. Myelin reactive T cells from MS patients have higher levels of Kv1.3 than either control antigen specific T cells or myelin reactive T cells from healthy volunteers. We have further demonstrated that the inflammatory infiltrate in MS brain tissue consists almost entirely of TEM and that these cells highly express Kv1.3. To better define the specific role of Kv1.3, we have generated a lentivirus construct that expresses a dominant negative (DN) form of Kv1.3 and have recently shown that transduction of CD4+ Tcell subsets with the Kv1.3DN both inhibits differentiation from TCM into TEM and mediates reversion of TEM into TCM. To identify target genes that contribute to these effects, we analyzed gene expression patterns by microarray, which showed significant differences in membrane microdomain, cell cycle, and differentiation genes as a result of Kv1.3 inhibition. The underlying hypothesis of this grant renewal is that Kv1.3 plays a major role in TEM cell derivation and biological function, and that selective blockade of this channel can reversibly inhibit the pathogenic consequences of these cells without compromising the TCM pool that is required for recall immune responses to pathogens. From our preliminary data, we are hypothesizing that Kv1.3 blockade disrupts T cell cycle and differentiation and will test this hypothesis in aim 1. The ultimate goal of this approach is to develop a new therapy for MS, and several pharmaceutical companies are currently generating Kv1.3 peptidyl blockers. Gaining a greater understanding of the in vivo effects will also be necessary for clinical translation. Towards this end, we will examine the effects of Kv1.3 inhibition on T cell infiltration, microglial activation, demyelination, and axon pathology in rat EAE models (Aim 2). The results of these experiments will allow us to better understand the therapeutic potential and safety of Kv1.3 blockade, and may have important implications for the design of upcoming human clinical trials of Kv1.3 blockers. Further, understanding basic mechanisms of T cell function will enhance our knowledge of how the immune system causes disease and allow us to develop novel strategies for correcting abnormal immune responses in diseases like MS.
The relevance of this research is in its ultimate goal to develop a new therapy for Multiple Sclerosis. The results of these experiments will allow us to better understand the therapeutic potential and safety of Kv1.3 blockade, and may have important implications for the design of upcoming human clinical trials of Kv1.3 blockers. Further, understanding basic mechanisms of T cell function will enhance our knowledge of how the immune system causes disease and allow us to develop novel strategies for correcting abnormal immune responses in diseases like MS.
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