Researchers Discover New Way To Fight Autoimmune Diseases

[Guest guest]

Source:

University of Pennsylvania School of Medicine

Date:

March 9, 2007

Researchers

Discover New Way To Fight Autoimmune Diseases

Multiple

sclerosis, diabetes, and arthritis are among a variety of autoimmune diseases

that are aggravated when one type of white blood cell, called the immune

regulatory cell, malfunctions.

In

humans, one cause of this malfunction is when a mutation in a gene called FOXP3

disables the immune cells’ ability to function. In

a new study published online next week in the Proceedings of the National

Academy of Sciences, researchers at the University of Pennsylvania School of

Medicine have discovered how to modify enzymes that act on the FOXP3 protein,

in turn making the regulatory immune cells work better. These

findings have important implications for treating autoimmune-related diseases.

“We

have uncovered a mechanism by which drugs could be developed to stabilize

immune regulatory cells in order to fight autoimmune diseases,” says

senior author Mark Greene, MD, PhD, the

Eckman Professor of Pathology and Laboratory Medicine. “There’s been little understanding about how

the FOXP3 protein actually works.” First author

Bin Li, PhD, a research associate in the Greene lab has been working on

elucidating this process since FOXP3’s discovery almost five years ago.

Li

discovered that the FOXP3 protein works via a complex set of enzymes. One set of those enzymes are called histone

deacetylases, or HDACs. These enzymes are linked to the FOXP3 protein in

association with another set of enzymes called histone

acetyl transferases that modify the FOXP3 proteins.

Li found

that when the histone acetyl transferases

are turned on, or when the histone deacetylases are turned off, the immune regulatory cells

work better and longer. As a consequence of the action

of the acetylating enzyme, the FOXP3 protein functions to turn off pathways

that would lead to autoimmune diseases.

“I

think this simple approach will revolutionize the treatment of autoimmune

diseases in humans because we have a new set of enzymatic drug targets as

opposed to the non-specific therapies we now use,” says Greene. Non-specific therapies include the use of steroids and

certain chemotherapy-like drugs that act on many cell types and have

significant side effects.

“Before

this work FOXP3 was thought essential for regulatory T-cell function, but how

FOXP3 worked was not known,” says Li. “Our research identifies a

critical mechanism. Based on this mechanism,

treatments could be developed to modulate this regulatory cell

population.”

“In

this line of investigation, we have learned how to turn on or off this

regulatory immune cell population – which is normally needed to prevent

autoimmune diseases – using drugs that are approved for other purposes,

but work on these enzymes” notes co-author Saouaf,

PhD, a research associate at Penn.

Li,

Greene, Saouaf and Penn

colleagues Wayne Hancock and Youhai Chen are now

extending this research directly to several mouse models of autoimmune

diseases.

Additional

co-authors are Arabinda Samanta,

Xiaomin Song, T. Iacono,

Bembas, Ran Tao, Samik

Basu, and Riley, all from Penn.

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