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The immune system's ability to police itself may offer a new method
of arresting the cells responsible for autoimmune diseases such as
multiple sclerosis and for the rejection of transplanted organs and
tissues, scientists at Dana-Farber Cancer Institute report in a study in
the May issue of the journal Immunity.
Because the technique utilizes the body's own mechanism for
controlling the immune system, it may prove more effective and less
prone to side effects than current therapies, which take a less direct
approach, the study authors indicate. Although the research was done in
mouse cells, it is likely to apply to humans because of strong
similarities between mouse and human immune cells.
"We found that when we block a key interaction between two types of
immune system cells, one of those types — which is often associated with
autoimmune disease and tissue rejection — is attacked and dies," says
senior author Harvey Cantor, MD, of Dana-Farber. "The fact that this
approach uses the body's natural system for regulating the immune
response encourages us that it can be the basis of an effective therapy
for a variety of immunological conditions."
Autoimmune disease and tissue rejection pose a complex challenge to
scientists. Both problems result from an attack by immune system cells —
which are trained to detect and destroy infected or diseased tissue —
on parts of the body where it isn't wanted. In the case of rejection,
they recognize transplanted tissue as foreign and mount an assault on
it. In autoimmune diseases, they attack the body's own tissue as through
it were foreign.
Conventional therapies for these conditions can have serious
drawbacks. Many of them rely on natural substances called antibodies,
which wedge inside "receptors" on immune system T cells. The coupling
blindfolds T cells to the presence of foreign or diseased tissue,
blunting their ability to spark an immune attack.
Antibody-based treatments fall short for a variety of reasons: the
antibodies often fail to fit securely inside T cells receptors, so the
immune response is only slightly reduced; or the antibodies succeed in
blocking the receptor, but that inadvertently causes the T cells to
launch a more ferocious attack. In other cases, antibodies work
too well, suppressing the entire immune system, rather than just a
portion of it, leaving patients susceptible to dangerous infections.
To overcome these problems, researchers have tried to harness the
body's natural system for quieting the immune response. One intriguing
approach involves the immune system's "natural killer," or NK, cells.
Scientists have long known that some NK cells can kill a class of T
cells — known as CD4 T cells — that have been activated to fight
infection, but that NK cells are often restrained from doing so.
Cantor and his colleagues theorized that when a tiny hook, or ligand,
called Qa-1–Qdm on activated CD4 T cells latches onto the NKG2A
receptor on NK cells, the T cells are protected from destruction. To
test this, they produced activated T cells that either lacked the
Qa-1–Qdm receptor or had a faulty version of it, preventing them from
binding to the NKG2A receptor. The result was that the T cells became
vulnerable to attack from a set of NK cells. Using an antibody to block
the connection between Qa-1–Qdm and NKG2A had the same result.
"Our findings suggest that it is possible to use antibodies to
trigger the body's own mechanism for suppressing the immune response,"
Cantor remarks. "The results serve as a proof of principle that this
approach can be applied to the treatment of conditions characterized by
an excessive or unwanted immune response."
While the work was done with mouse cells, the Qa-1–Qdm ligand has the
same shape and structure in human and mouse T cells, raising hopes that
the approach will prove effective in humans as well, adds Cantor, who
is also a professor of pathology at Harvard Medical School.
The research was supported by grants from the National Institutes of
Health, the National Multiple Sclerosis Society, the Claudia Adams Barr
Foundation, and a fellowship from Taiho Pharmaceuticals of Japan.
The lead author of the study is Linrong Lu, PhD, of Dana-Farber.
Co-authors include Koichi Ikizawa, PhD, Dan Hu, PhD, Miriam Werneck, and
Kai Wucherpfennig, MD, PhD, all of Dana-Farber.
Dana-Farber Cancer Institute (www.dana-farber.org)
is a principal teaching affiliate of the Harvard Medical School and is
among the leading cancer research and care centers in the United States.
It is a founding member of the Dana-Farber/Harvard Cancer Center
(DF/HCC), designated a comprehensive cancer center by the National