Old Leprosy Drug Shows Promise for Treating Autoimmune Diseases

Clofazimine, one of the few drugs used for treatment of leprosy, has been found to exert a strong immunomodulatory effect on T cells, which renders it a promising candidate drug for treatment of autoimmune diseases such as multiple sclerosis.

Investigators at Johns Hopkins University (Baltimore, MD, USA) screened more than 3,000 compounds from the Johns Hopkins Drug Library for the ability to inhibit intracellular T cell receptor-mediated signaling, a key factor in the development of autoimmune disorders.

They reported in the December 23, 2008, online edition of the journal Public Library of Science (PLoS One) that clofazimine, a fat-soluble riminophenazine dye used in combination with rifampicin and dapsone as multidrug therapy for the treatment of leprosy, inhibited the human potassium channel Kv1.3. This protein plays an essential role in effector memory T cells and has been implicated in several important autoimmune diseases including multiple sclerosis, psoriasis, and type I diabetes. By selectively blocking Kvl.3 channel activity, clofazimine perturbed the oscillation frequency of the calcium-release activated calcium channel, which led to the inhibition of the calcineurin-NFAT (nuclear factor of activated T-cells) signaling pathway. Furthermore, clofazimine was found to be effective in blocking human T cell-mediated skin graft rejection in an animal model in vivo.

"This let us conclude that clofazimine was blocking the calcium influx into the immune cells," said senior author Dr. Jun O. Liu, professor of pharmacology and molecular science at Johns Hopkins University. "Without enough calcium getting inside a cell, the signaling pathway that turns on the immune response was short-circuited."

"Until now, clofazimine's presumed target was not human cells, but bacteria," said Dr.Liu. "But we discovered the drug has a tremendous effect on human immune cells that are heavily involved in both the initiation and execution of an effective immune response. We never expected that an old antibiotic would hit this target that has been implicated in multiple sclerosis, psoriasis, and type I diabetes. People have been working for years and spending tens of millions of dollars on developing a drug to inhibit a specific molecular target involved in these diseases, and here, we have a safe, known drug that hits that target."

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