A New Lead for Autoimmune Disease

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A New Lead for Autoimmune Disease

_http://www.newswise.com/p/articles/view/552951/_

(http://www.newswise.com/p/articles/view/552951/)

 

Description

A major challenge in treating autoimmune disorders has been suppressing

inflammatory attacks without generally suppressing immune function. Now, a

drug from Chinese medicine shows potential, easing multiple-sclerosis-like

autoimmune disease in mice. In mice and humans, it inhibited development of

Th17 cells, newly-recognized immune cells recently implicated in multiple

autoimmune disorders.

 

 

Newswise — 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.

 

 

Founded in 1953, the Program in Molecular and Cellular Medicine and the

Immune Disease Institute (PCMM/IDI) is a non-profit research institution in

Boston, MA, recognized worldwide for its discoveries that increase the

body's ability to fight disease and to heal. With the aim of increasing

collaborations and scientific synergies, Immune Disease Institute and

Children*s

Hospital Boston have entered into an affiliation whereby IDI joins seven

other interdisciplinary programs as the Program in Cellular and Molecular

Medicine. PCMM/IDI is also academically affiliated with Harvard Medical School,

and its investigators hold appointments in departments of the medical

school. The breakthroughs of PCMM/IDI scientists are greatly increasing our

understanding of the influence of immune defense and inflammation on biomedical

discovery, healthcare, and disease management. For more information about

PCMM/IDI and our history as the Center for Blood Research visit:

_www.idi.harvard.edu_ (http://www.idi.harvard.edu) .

 

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