New Treatment For Inflammatory Bowel Disease
Shown By UCSD, Japanese And Israeli Researchers
By Sue Pondrom
therapy utilizing proteins called type 1 interferon IFN-alpha
and IFN-beta (IFN-a/ß) has been shown by researchers at
the UCSD School of Medicine and their colleagues in Japan and
Israel to offer relief in mouse models of Crohn’s disease
and ulcerative colitis, the two major forms of the painful,
chronic condition called inflammatory bowel disease (IBD) that
affects nearly 1 million Americans.
Published in the March
2005 issue of the Journal of Clinical Investigation
(JCI), the study provides the first description of the molecular
mechanism by which IFN-a/ß inhibits the severity of colitis
and maintains intestinal homeostasis, or the “constant
state” of the gut, by suppressing pro-inflammatory activity
by the immune system macrophages.
therapy has been tried in recent clinical trials, along with
other anti-inflammatory treatments, researchers have not understood
how or why IFN-a/ß might work as an IBD treatment,”
said Eyal Raz, M.D., UCSD professor of medicine and the study’s
senior author. “Our study describes how activated IFN-a/ß
plays a protective role in colonic inflammation.”
The study’s first
author, Kyoko Katakura, M.D, Department of Medicine II, Fukushima,
Japan, added that the team’s results point to an important
protective and potential therapeutic role for IFN-a/ß.
In an accompanying
Commentary in the March issue of JCI, German researchers Stefan
Wirtz and Markus F. Neurath noted that the results “suggest
that strategies to modulate innate immunity may be of therapeutic
value.” They added that “It is astonishing to realize
that in spite of the existence of clinical trials on the use
of IFN-a/ß in the treatment of UC (ulcerative colitis),
there is only very limited information about their expression
and biological function in the immune system of the gut.”
The Raz team discovered
the role of IFN-a/ß through their continuing studies of
an immune system molecule called Toll-like receptor 9 (TLR9).
In previous research* the researchers had shown
that TLR9 initiated an anti-inflammatory program to ease colitis
in experimental animals. In the new study, the investigators
again utilized mouse models to explore how TLR9 eases inflammation.
This time, however, they found differing reactions in two strains
Agents that activate
TLR9 were given to the two different groups of mice that appear
similar, but are from strains that make them genetically different.
The TLR9 activators given to one of the groups, called RAG mice,
inhibited the severity of experimental colitis, but had no effect
on the other group of mice, called SCID mice.
To understand why the
mice reacted differently, the researchers used a variety of
scientific approaches to explore the cellular and molecule events
that caused one strain to respond to therapy and the other to
be resistant. They determined that TLR9-induced protection occurs
when the proteins IFN-a/ß were activated. The resistance
to protection in the SCID mice was due to a mutation that impairs
IFN-a/ß signaling in these mice. Additional experiments
with mice developed without IFN-a/ß further verified the
proteins’ role in intestinal homeostasis.
The study was funded
by the National Institutes of Health. Additional authors included
first author Kyoko Katakura, M.D, Department of Medicine II,
Fukushima, Japan, Jongdae Lee, Ph.D., and Lars Eckmann, M.D.,
UCSD Department of Medicine; and Daniel Rachmilewitz, M.D.,
professor and head of the Division of Internal Medicine, Shaare
Zedek Medical Center, Jerusalem, Israel.
Sue Pondrom (619) 543-6163