Researchers from the National Institute of Arthritis and
Musculoskeletal and Skin Diseases (NIAMS), a part of the
National Institutes of Health (NIH), have identified a
promising new target for autoimmune disease treatment - a
cell-surface receptor called DR3.
Their research in mice, published on line in the journal
Immunity, suggests that blocking this receptor could
slow or stop the damaging inflammation characteristic of
autoimmune diseases, potentially without leaving the body
vulnerable to serious infections, as many current therapies
do.
DR3 is a protein on the surface of cells. It is a member
of the tumor necrosis factor (TNF) family of receptors,
which bind to molecules related to TNF, a cell-signaling
protein that promotes inflammation. Many of today's most
potent treatments for inflammatory diseases, such as
rheumatoid arthritis and psoriasis, interfere with the
action of TNF, thereby blocking inflammation. Since current
anti-TNF therapies don?t work in all autoimmune diseases,
however, the researchers turned to the study of DR3, which
is a close relative of TNFR1, the main receptor for TNF.
Working with mouse models of asthma and multiple
sclerosis, both immune system diseases, the researchers
found that mice engineered to lack DR3 were resistant to
those diseases. "The implication is that blocking DR3 in
mice, and possibly in humans, is a potential therapy for
these diseases and perhaps others in which the immune system
goes awry,said Richard Siegel, M.D., Ph.D., a scientist in
the NIAMS' Immunoregulation Group, who led the research
effort.
While closely related to TNFR1, DR3 is expressed in T
cells, a different kind of immune cell (a white blood cell
that identifies and fights infection) than those that
express TNFR1, Dr. Siegel said. The NIAMS group collaborated
with a laboratory in Cardiff, Wales, which had generated
genetically engineered mice deficient in DR3, as well as
with a research group at the NIH's National Institute of
Allergy and Infectious Diseases (NIAID), which has developed
mouse models of disease with strong T cell components, such
as asthma and multiple sclerosis. "These findings open up
new avenues for therapy of these two diseases as well as to
other autoimmune diseases in which T cells play a role in
causing or perpetuating the disease,said Siegel.
The researchers hope that DR3-blocking agents will be
effective anti-inflammatory treatments someday. Siegel noted
that if they were to be used in rheumatic diseases, they
would be a complement to strategies that block TNF because
they hit a different arm of the immune system. "It could be
potentially synergistic or complementary", he said.
Of critical importance, the NIAMS scientists found that
removing DR3 did not appear to suppress the immune response
or the ability to fight infection within the mice - a
problem with many other treatments for autoimmune disease.
"We could see the effect of DR3 deficiency in the diseased
organ, but when we looked systemically at the immune
response at other places in the mouse, it was barely
affected,said Dr. Siegel. The group's findings suggest that
DR3-blocking agents might be more effective at specifically
treating autoimmune disease without breaking down the body's
defenses against infections, a long-sought goal of
researchers in the field.
