A collaborative research team led by Dr. Mark Sundrud at the Department of Pathology, Harvard Medical School and Immune Disease Institute, Boston, Mass., has reported that halofuginone, a compound derived from hydrangea root (Dichroa febrifuga), halts the progression of experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS), in C57BL/6J (B6, 000664) mice (Sundrud et al. 2009). Importantly, unlike other therapies for autoimmune diseases, halofuginone does not have the undesirable effect of suppressing the immune system.
MS is an inflammatory demyelinating disease of the central nervous system, generally thought to involve an autoimmune reaction by myelin-specific CD4+ T helper cells (Friese et al. 2006). It is the most common cause of acquired disability in adults (Kuhlmann et al. 2006). Most people with MS are diagnosed between the ages of 20 and 50 years old. MS affects two to three times as many women as men and is more common among people with northern European ancestry. Approximately 400,000 Americans have MS, and it may affect as many as 2.5 million people worldwide (National Multiple Sclerosis Society). MS is thought to be caused by complex interactions among the immune system, the environment, infectious diseases and genetics. In a genome-wide study, Hafler et al. (Hafler et al., 2007) reported that alleles of IL2RA and IL7RA and those in the HLA locus are heritable risk factors for MS.
Experimental autoimmune encephalomyelitis
Model organisms do not spontaneously develop multiple sclerosis. In mice, the disease is approximated by inducing a condition known as experimental autoimmune encephalomyelitis (EAE), usually with injections of myelin peptides, such as myelin basic protein (MBP), proteolipid protein (PLP), or myelin oligodendrocyte glycoprotein (MOG), in complete Freund’s adjuvant. Just as MS susceptibility varies in humans, EAE susceptibility and severity differ in mice, probably due to varying expression patterns of several chemokines and unique genetic differences among strains (see: Blom, van Lent, Holthuysen, and van den Berg, 1999; Gold, Linington, Lassmann, 2006; Teuscher, Hickey, Grafer, and Tung, 1998) . In B6 mice, (e.g. C57BL/6J – 000664), the most commonly used EAE model, MOG induces chronic EAE within one to two weeks (Matsushita et al. 2006).
The promise of halofuginone
Mammals generate several types of CD4+ T helper cells, including TH1, TH2, Treg, and TH17 cells. TH1 and TH2 cells secrete cytokines that activate immune responses to bacteria and other infectious agents (TH1) or as part of an allergic response (TH2); Treg cells prevent other T cells from attacking the body. TH17 cells mediate immune responses to certain bacteria and fungi by producing the pro-inflammatory cytokine interleukin-17 (IL17) (Blander and Amsen 2009).
However, TH17 cells are gaining recognition as important and broad mediators of autoimmunity. Hence autoimmune disease researchers are keenly interested in discovering drugs that specifically target TH17 cells. Halofuginone, an herb used in traditional Chinese medicine and to treat malaria and scleroderma, comes close to being such a drug. According to Sundrud and his team, halofuginone selectively inhibits the differentiation of TH17 cells from mice and humans, but has only minor effects on TH1, TH2, and Treg cell lineages. Unfortunately, halofuginone does not affect the function of already developed TH17 cells, a potential drawback to its use as an MS therapy because autoimmune disorders usually manifest themselves after auto-aggressive T cells develop. Furthermore, TH17 cells produce IL10 and IL22, both of which function in immune tolerance and tissue repair (Blander and Amsen 2009). Nevertheless, the benefits of halofuginone may well outweigh its shortcomings, especially if its utility can be expanded to prevent multiple sclerosis, a disease that affects so many people and for which few therapies currently exist.
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