BOSTON, Mass., USA: Researchers from the Harvard School of Medicine have discovered that a chemical compound found in a traditional Chinese root extract affects autoimmunity by preventing a harmful class of immune cells from developing.
Dichroa febrifuga, commonly known as chang shan, is one of the 50 fundamental herbs of traditional Chinese medicine and has been used as a malarial agent for more than 2,000 years. In the course of a study, Malcolm Whitman, Professor of Developmental Biology at Harvard School of Medicine, and his colleagues found that halofuginone (HF), a natural quinazolinone alkaloid occurring in the herb could be used to treat autoimmune disorders.
Their findings about the small-molecule compound could also be relevant for dental autoimmune immune disorders, such as chronic ulcerative stomatitis. U.S. researchers found in 2011 that painful oral lesions associated with the disease are most likely caused by an autoimmune response.
Earlier studies conducted by Whitman’s team in 2009 had already demonstrated that HF activates a response pathway that blocks the development of harmful T helper 17 cells (Th17), which play a key role in autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, and that in this regard HF is very selective in its effect. A series of experiments demonstrated that HF inhibits the development of Th17 cells, but does not affect other kinds of T-cells involved in regular immune function.
HF acts by triggering a biochemical pathway known as amino-acid starvation response (ARR), which typically prevents cells from forming when amino acids are in short supply. By depleting amino acids, researchers were able to induce ARR and inhibit differentiation of Th17 cells.
In the current study, Whitman’s research team investigated how HF activates the AAR pathway by looking at the most basic process that cells use to translate DNA into the amino-acid chain that makes up a protein. Experiments demonstrated that HF targets a particular enzyme that incorporates the amino acid proline into proteins. It was observed that whenever proline was in short supply, ARR kicked in and produced the therapeutic effects of HF treatment.
According to Whitman, “This compound could inspire novel therapeutic approaches to a variety of autoimmune disorders.”
With regard to the treatment of autoimmune disorders, the challenge has been suppressing inflammatory attacks by the immune system on body tissue without generally suppressing immune function. In instances of chronic ulcerative stomatitis, treatment was only successful using hydroxychloroquine, a prescription drug primarily used to prevent malaria and rheumatoid arthritis.
“This study is an existing example of how solving the molecular mechanism of traditional herbal medicine can lead both to new insights into physiological regulation and to novel approaches to the treatment of diseases,” said Tracy Kelly, an instructor in Whitman’s lab.
However, researchers do not yet fully understand the role that amino-acid limitation plays in disease response or why restricting proline inhibits Th17 cell production.