A small molecule better known for its anti-malarial properties can block the birth of the immune cells involved in autoimmune diseases without blocking crucial infection-fighting cells, report Harvard Medical and Dental School researchers. The findings in the June 5 Science suggest a potentially new therapeutic approach for some autoimmune diseases.
The molecule, called halofuginone, is derived from roots of a plant in the hydrangea family, Dichroa febrifuga, or blue evergreen hydrangea, which grows in Asia and is used in Chinese herbal medicine.
For this study, instructor Tracy Keller and professor Malcolm Whitman, co-authors from the Dental School’s Developmental Biology Department, were wondering how to explain the selective effects of halofuginone on tissue repair—healing wounds while preventing scar tissue formation. They turned to coauthors Anjana Rao, HMS professor of pathology at the Immune Disease Institute and Children’s Hospital Boston, and postdoctoral fellow Mark Sundrud, who were casting about for a way to explain how functionally opposite types of T cells could come from the same precursors receiving the same signal from the cytokine TGF-beta.
In the body, one common precursor T cell can give rise to both tissue-protective T regulatory, or Treg, cells and the inflammatory T cell type known as T helper 17, or Th17, cells, which play a prominent role in many autoimmune-related disorders, such as multiple sclerosis, inflammatory bowel disease, and psoriasis.
Th17 cells were discovered about three years ago by several groups, including another team at HMS (Focus, June 9, 2006).
In cultured mouse and human T cells, halofuginone thwarted Th17 cells from emerging without interfering with tissue-protective Treg cells, said Sundrud, first author of the paper. In a mouse model of multiple sclerosis, halofuginone protected against autoimmunity driven by Th17 cells.
Equally important was a major clue about how the molecule works. Halofuginone turned on the same set of genes that cells turn on as a stress response to low levels of amino acids. In fact, excess amino acids could override the effects of the compound.
The researchers do not yet know if some safer variation of halofuginone itself could be a useful drug or whether the secrets it helps researchers unlock about how the immune system works might lead to new treatments for autoimmune diseases.
“We don’t yet fully understand how halofuginone works,” Sundrud said. “In order to design safe and effective therapeutics, we have to know a lot more.”
Students may contact Malcolm Whitman at mwhitman@hms.harvard.edu for more information.
Conflict Disclosure: HMS and several coauthors have filed patent applications concerning the use of halofuginone and its derivatives to inhibit Th17 cell differentiation.
Funding Sources: The National Institutes of Health, the Harvard Accelerator Fund, the Juvenile Diabetes Research Foundation, the Irvington Institute fellowship program of the Cancer Research Institute, the Portuguese Foundation for Science and Technology; the content of the work is the responsibility solely of the authors.
