||One cause of an immune regulatory
cell malfunction, which underlies many autoimmune diseases,
is when a mutation in a gene called FOXP3 disables
the immune cells’ ability to function.
|| Researchers at the University
of Pennsylvania School of Medicine found that
when enzymes known as histone acetyl transferases
are turned on, or when the histone deacetylases are turned
off, the immune regulatory cells work better and longer.
||The research will be published online
next week in the Proceedings of the National Academy
(PHILADELPHIA) – 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.
Human regulatory T-cells viewed using
fluorescence microscopy after immunostaining
Click on thumbnail
to view full-size image
“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 five years ago.
Li discovered that the FOXP3 protein works via a complex set of
enzymes. One set of those enzymes are called histone
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.
Additional co-authors are Arabinda Samanta, Xiaomin Song, Kathryn
T. Iacono, Kathryn Bembas, Ran Tao, Samik
Basu, and James
all from Penn.
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