Drug Discovery Opinion

A major challenge in treating autoimmune disease is to prevent tissue damage without generalised immunosuppression. US researchers now suggest that selective damping down of the T_H17 response using compounds such as halofuginone may provide an answer to this challenge.

Writing in the June 5^th edition of the journal Science, they show that halofuginone specifically inhibits the development of T_H17 cells which are believed to play a key role in tissue injury in autoimmune diseases such as inflammatory bowel disease, multiple sclerosis, type 1 diabetes, eczema and psoriasis. When halofuginone was added to cultures of naïve mouse CD4⁺ T-cells containing cytokines that would normally induce differentiation into T_H17 cells, the number of T_H17 cells – but not T_H1, T_H2 or T regulatory cells – was substantially reduced. In cultured human CD4⁺ T-cells, halofuginone also selectively suppressed levels of IL-17, the main cytokine produced by T_H17 cells. In mice with experimental autoimmune encephalitis (EAE), an artificially-induced immune disease resembling multiple sclerosis and marked by infiltration of T_H17 cells into the central nervous system, treatment with low doses of halofuginone significantly reduced both the development of EAE and its severity.

To understand how halofuginone works, the researchers looked at alterations in gene expression in response to drug treatment and found that a cytoprotective signalling pathway, the amino acid starvation response (AAR), was activated. Inhibition of T_H17 differentiation by halofuginone could be overcome by the addition of excess amino acids and was mimicked by AAR activation in response to selective amino acid depletion.

Halofuginone is a synthetic analogue of febrifugine, the active principal of the Chinese herb, chang shan (Dichroa febrifuga), which has been used to treat fever and malaria for more than 2000 years. Febrifugine itself causes severe emesis and gastrointestinal irritation and, in the 1960s, a number of analogues – including halofuginone – were synthesized by U.S. Army scientists looking for novel antimalarials. Halofuginone also inhibits synthesis of collagenase and collagen type 1 and underwent clinical trials for the treatment of scleroderma, a chronic, autoimmune condition of the connective tissue. In animal husbandry, halofuginone (as Stenerol®) is used prophylactically to control coccidial infection in poultry flocks.

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