Saturday, March 10, 2007

Penn Researchers Identify New Molecular Path To Fight Autoimmune Diseases

Type 1 diabetes, rheumatoid arthritis and multiple sclerosis are a few of the different autoimmune diseases that are aggravated when a certain type of white blood cell (the immune regulatory cell) fails to work properly. A cause of this malfunction in humans is when a mutation in the FOXP3 gene disables the immune cells' ability to properly function, in effect, disabling the immune system's ability to identify self vs. non-self. Although FOXP3 has been known about for several years, the manner that it functions was not. But in a brand new study published online in the Proceedings of the National Academy of Sciences, researchers at the University of Pennsylvania School of Medicine have apparently discovered a way to modify how enzymes act on the FOXP3 protein, in essence, enabling them to re-educate how the regulatory immune cells actually work. It is possible that these findings could have dramatic implications for treating a variety of different autoimmune diseases, including type 1 diabetes.

"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 John 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 5 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 Sandra 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.


Bin Li, Arabinda Samanta, Xiaomin Song, Kathryn T. Iacono, Kathryn Bembas, Ran Tao, Samik Basu, James L. Riley, Wayne W. Hancock, Yuan Shen, Sandra J. Saouaf, and Mark I. Greene; "FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression"; PNAS published March 7, 2007, 10.1073/pnas.0700298104 (Immunology).

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