July 28, 2009

Chinese Herb Offers Hope to MS Patients

A collaborative research team led by Dr. Mark Sundrud at the Department of Pathology, Harvard Medical School and Immune Disease Institute, Boston, MA, 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.

Multiple Sclerosis

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 DA 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 MS. 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 differs among mouse strains, probably due to varying expression patterns of several chemokines and unique genetic differences among strains. In the B6 mouse, the most commonly used EAE model, MOG induces chronic EAE within one to two weeks (Matsushita et al. 2006).

In addition to C57BL/6J, several other JAX® Mice strains, including SJL/J (000686), PL/J (000680), BALB/cJ (000651), BALB/cByJ (001026), and B10.RIII-H2r H2-T18b/(71NS)SnJ (000457) have been used to research EAE (Blom et al. 1999; Gold et al. 2006). Teuscher et al. (1998) found that whereas BALB/cJ mice are resistant to EAE, BALB/cByJ mice are susceptible. Blom et al. (1999) found that EAE susceptibility in B10.RIII-H2r H2-T18b/(71NS)SnJ mice is associated with the major histocompatibility complex (MHC) allele, H2r, the T cell receptor V β8 chain, and other non MHC loci.

The Promise of Halofluginone

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 proinflammatory 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 mouse and human TH17 cells 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 autoaggressive 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 MS, a disease that affects so many people and for which few therapies currently exist.

Are you researching an autoimmune disease? You might benefit from a complimentary copy of our Autoimmune Disease Resource Manual. It describes many JAX® Mice models and services that facilitate researching some of the most common autoimmune diseases, including alopecia areata, inflammatory bowel disease, lupus, multiple sclerosis, and rheumatoid arthritis. To request a copy of this informative manual, simply fill out our literature request form.

Looking for a convenient way to test your anti-inflammatory compounds in mouse models of autoimmune disease? JAX® Services can help you get started. Contact them at 1-800-422-6423, +1-207-288-5845, or jaxservices@jax.org.

References

Blander JM, Amsen D. 2009. Amino acid addiction. Science 324:1282-3.

Blom AB, van Lent PL, Holthuysen AE, van den Berg WB. 1999. Immune complexes, but not streptococcal cell walls or zymosan, cause chronic arthritis in mouse strains susceptible for collagen type II auto-immune arthritis.
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Friese MA, Montalban X, Willcox N, Bell JI, Martin R, Fugger L. 2006. The value of animal models for drug development in multiple sclerosis. Brain 129(Pt 8):1940-52.

Gold R, Linington C, Lassmann H. 2006. Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 129(Pt 8):1953-71.

Hafler DA et al. International Multiple Sclerosis Genetics Consortium. 2007. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 357:851-62.

Matsushita T, Fujimoto M, Hasegawa M, Komura K, Takehara K, Tedder TF, Sato S. 2006. Inhibitory role of CD19 in the progression of experimental autoimmune encephalomyelitis by regulating cytokine response. Am J Pathol 168:812-21.

Sundrud MS, Koralov SB, Feuerer M, Calado DP, Kozhaya AE, Rhule-Smith A, Lefebvre RE, Unutmaz D, Mazitschek R, Waldner H, Whitman M, Keller T, Rao A. 2009. Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response. Science 324:1334-8.

Teuscher C, Hickey WF, Grafer CM, Tung KS. 1998. A common immunoregulatory locus controls susceptibility to actively induced experimental allergic encephalomyelitis and experimental allergic orchitis in BALB/c mice. J Immunol 160:2751-6.