New Lead For Autoimmune Disease From Chinese Medicine

New Lead For Autoimmune Disease From Chinese Medicine


ScienceDaily (June 8, 2009) ? A drug derived from the hydrangea root, used
for centuries in traditional Chinese medicine, shows promise in treating
autoimmune disorders, report researchers from the Program in Cellular and
Molecular Medicine and the Immune Disease Institute at Children's Hospital
Boston (PCMM/IDI), along with the Harvard School of Dental Medicine. In the
June 5 edition of Science, they show that a small-molecule compound known as
halofuginone inhibits the development of Th17 cells, immune cells recently
recognized as important players in autoimmune disease, without altering
other kinds of T cells involved in normal immune function. They further
demonstrate that halofuginone reduces disease pathology in a mouse model of
autoimmunity.


Currently there is no good treatment for autoimmune disorders; the challenge
has been suppressing inflammatory attacks by the immune system on body
tissues without generally suppressing immune function (thereby increasing
risk of infections). The main treatment is antibodies that neutralize
cytokines, chemical messengers produced by T cells that regulate immune
function and inflammatory responses. However, antibodies are expensive, must
be given intravenously and don't address the root cause of disease, simply
sopping up cytokines rather than stopping their production; patients must
therefore receive frequent intravenous infusions to keep inflammation in
check. Powerful immune-suppressing drugs are sometimes used as a last
resort, but patients are left at risk for life-threatening infections and
other serious side effects.


Through a series of experiments, the researchers show that halofuginone
prevents the development of Th17 cells in both mice and humans, halts the
disease process they trigger, and is selective in its effects. It also has
the potential to be taken orally. "This is really the first description of a
small molecule that interferes with autoimmune pathology but is not a
general immune suppressant," says Mark Sundrud, PhD, of the PCMM/IDI, the
study's first author.


Recognized only since 2006, Th17 cells have been implicated in a variety of
autoimmune disorders including inflammatory bowel disease, rheumatoid
arthritis, multiple sclerosis, type 1 diabetes, eczema and psoriasis. They
are genetically distinct from the other major categories of T-cells (Th1,
Th2 and T-regulatory cells).


Th17 cells normally differentiate from "naïve" CD4+ T cells, but when
Sundrud and colleagues cultured mouse CD4+ T-cells along with cytokines that
normally induce Th17 development, there was a pronounced decrease in Th17
cells ? but not in Th1, Th2 or T regulatory cells ? when halofuginone was
added. Similarly, in cultured human CD4+ T-cells, halofuginone selectively
suppressed production of IL-17, the principal cytokine made by Th17 cells.


And in mice with experimental autoimmune encephalitis (EAE), an
artificially-induced immune disease resembling multiple sclerosis in humans,
and marked by infiltration of Th17 cells into the central nervous system,
low-dose halofuginone treatment significantly reduced both the development
of EAE and its severity. (In mice with another form of EAE that doesn't
involve Th17 cells, halofuginone had no effect.)


Wondering how halofuginone works, the researchers did microarray studies of
the halofuginone-treated cells to examine patterns of gene expression in
response to the drug. Unexpectedly, many genes involved in stress responses
were turned on. Eventually, they found that halofuginone acts by activating
a biochemical pathway known as the "amino acid starvation response," or AAR,
which typically protects cells when amino acids, essential building blocks
of proteins, are in short supply. When excess amino acids were added to
cultured T-cells exposed to halofuginone, the AAR didn't switch on, and Th17
cells were able to develop. Conversely, the researchers were able to inhibit
Th17 differentiation simply by depleting amino acids, thereby inducing the
AAR.


Why would the AAR prevent Th17 cells from forming? The researchers propose
that the AAR has an energy-saving function, slowing down a cell's building
activities to conserve amino acids. "When a cell senses amino acid
deprivation, it tries to conserve amino acids by preventing specific types
of responses that are energetically expensive," says Sundrud. "In inflamed
tissues, a lot of cells are producing a lot of protein, so it would make
sense that a cell with amino acid deprivation would want to block signals
that promote inflammation."


Halofuginine is one of the 50 fundamental herbs of traditional Chinese
medicine, and has been used as an antimalarial agent. Decades ago, the U.S.
Army tried to improve upon its antimalarial properties, without success. It
has been in clinical trials for scleroderma, but because it is now in the
public domain, the pharmaceutical industry has not shown interest in further
developing it therapeutically.


But halofuginone, or some yet-to-be developed derivative compound, could
potentially be used to address any autoimmune or inflammatory disease
related to Th17 cells by activating the AAR, the researchers say.


"Remarkably, halofuginone evokes the AAR in all cells but selectively
inhibits T-cell inflammatory responses," says Anjana Rao, PhD, of the
PCMM/IDI, a senior investigator on the study. "This recalls the actions of
cyclosporin A and FK506, two other immunosuppressive drugs that block the
activity of calcineurin. Calcineurin is present in all cells, but
selectively prevents the rejection of heart, lung, liver and bone marrow
transplants when given to patients. These drugs revolutionized transplant
medicine when they were introduced over 20 years ago, and halofuginone may
herald a revolution in the treatment of certain types of
autoimmune/inflammatory diseases."


Malcolm Whitman, PhD and Tracy Keller, PhD, of the Harvard School of Dental
Medicine, and Anjana Rao, PhD, of the PCMM/IDI, were the study's senior
investigators. The study was funded by grants from the National Institutes
of Health, the Juvenile Diabetes Research Foundation, and the Cancer
Research Institute.
Adapted from materials provided by Children's Hospital Boston.


Children's Hospital Boston (2009, June 8). New Lead For Autoimmune Disease
From Chinese Medicine. ScienceDaily. Retrieved June 8, 2009, from
http://www.sciencedaily.com­; /releases/2009/06/090604144328.htm


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