Clofazimine Inhibits Human Kv1.3 Potassium Channel by Perturbing Calcium Oscillation in T Lymphocytes

The Kv1.3 potassium channel plays an essential role in effector memory T cells and has been implicated in several important autoimmune diseases including multiple sclerosis, psoriasis and type 1 diabetes. A number of potent small molecule inhibitors of Kv1.3 channel have been reported, some of which were found to be effective in various animal models of autoimmune diseases. We report herein the identification of clofazimine, a known anti-mycobacterial drug, as a novel inhibitor of human Kv1.3. Clofazimine was initially identified as an inhibitor of intracellular T cell receptor-mediated signaling leading to the transcriptional activation of human interleukin-2 gene in T cells from a screen of the Johns Hopkins Drug Library. A systematic mechanistic deconvolution revealed that clofazimine selectively blocked the Kv1.3 channel activity, perturbing the oscillation frequency of the calcium-release activated calcium channel, which in turn led to the inhibition of the calcineurin-NFAT signaling pathway. These effects of clofazimine provide the first line of experimental evidence in support of a causal relationship between Kv1.3 and calcium oscillation in human T cells. Furthermore, clofazimine was found to be effective in blocking human T cell-mediated skin graft rejection in an animal model in vivo. Together, these results suggest that clofazimine is a promising immunomodulatory drug candidate for treating a variety of autoimmune disorders

Remote Sensing Analysis of Vegetation Recovery following Short-Interval Fires in Southern California Shrublands

Increased fire frequency has been shown to promote alien plant invasions in the western United States, resulting in persistent vegetation type change. Short interval fires are widely considered to be detrimental to reestablishment of shrub species in southern California chaparral, facilitating the invasion of exotic annuals and producing "type conversion". However, supporting evidence for type conversion has largely been at local, site scales and over short post-fire time scales. Type conversion has not been shown to be persistent or widespread in chaparral, and past range improvement studies present evidence that chaparral type conversion may be difficult and a relatively rare phenomenon across the landscape. With the aid of remote sensing data covering coastal southern California and a historical wildfire dataset, the effects of short interval fires (<8 years) on chaparral recovery were evaluated by comparing areas that burned twice to adjacent areas burned only once. Twelve pairs of once- and twice-burned areas were compared using normalized burn ratio (NBR) distributions. Correlations between measures of recovery and explanatory factors (fire history, climate and elevation) were analyzed by linear regression. Reduced vegetation cover was found in some lower elevation areas that were burned twice in short interval fires, where non-sprouting species are more common. However, extensive type conversion of chaparral to grassland was not evident in this study. Most variables, with the exception of elevation, were moderately or poorly correlated with differences in vegetation recovery