Halofuginone Inhibits TH17 Cells and Suppresses Autoimmune Inflammation

A major challenge in developing drugs to treat autoimmune diseases has been to inhibit TH17 differentiation and activity without generally suppressing the immune system and thereby increasing risk of infections.

Investigators from Harvard University (Cambridge, MA, USA) studied the effect of halofuginone, a drug derived from the hydrangea root, which has been used for centuries in traditional Chinese medicine to treat malaria and autoimmune disorders such as scleroderma. They reported in the June 5, 2009, issue of the journal Science that when used to treat human or mouse T-cells growing in culture, halofuginone selectively inhibited TH17 differentiation by activating a the amino acid starvation response (AAR) signaling pathway, which typically protects cells when amino acids are in short supply.

Inhibition of TH17 differentiation by halofuginone could be reversed by the addition of excess amino acids, and its action could be mimicked by selective amino acid depletion.

When tested in mice with experimental autoimmune encephalitis (EAE), an artificially induced immune disease resembling multiple sclerosis in humans, and marked by infiltration of Th17 cells into the central nervous system, low-dose halofuginone treatment significantly reduced both the development of EAE and its severity. Mice suffering from a different form of EAE lacking Th17 cell involvement did not respond to halofuginone treatment.

"Remarkably, halofuginone evokes the AAR in all cells but selectively inhibits T-cell inflammatory responses,” said senior author Dr. Anjana Rao, professor of cellular medicine at Harvard University. "This recalls the actions of cyclosporin A and FK506, two other immunosuppressive drugs that block the activity of calcineurin. Calcineurin is present in all cells, but selectively prevents the rejection of heart, lung, liver, and bone marrow transplants when given to patients. These drugs revolutionized transplant medicine when they were introduced over 20 years ago, and halofuginone may herald a revolution in the treatment of certain types of autoimmune/inflammatory diseases.”

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