Autoimmunity squelched without
immunosuppression
BY EVELYN STRAUSS
Usually, the immune system adheres to a behavioral
code that demands respect for the body's healthy cells
and restricts attack to cancers and harmful microbial
invaders. But sometimes immune cells break the rules and
turn against normal parts of the body. When this happens,
people experience the devastating effects of autoimmune
disease.
Investigators in the School of Medicine have succeeded
in reforming delinquent immune cells that have turned
against the body they are meant to protect. The
researchers forced the misbehaving cells to carry the
blueprint for a gene that squelches the destructive
response. Their findings revealed that mice destined to
have an autoimmune disease benefit significantly from
this treatment.
"This is the first time anyone has shown that
these molecules can be delivered to a specific site,
bypassing problems associated with delivering an
immunosuppressive drug to the entire body," said
Michael Shaw, a postdoctoral fellow in the laboratory of
Dr. Garry Fathman. "It means that we may be able to
have the benefit of current therapies for autoimmune
disease without the side effects of global
immunosuppression. Right now, patients' immune systems
are suppressed to such an extent that they are much more
susceptible to infections and some cancers. And there are
also a host of other side effects, including obesity and
loss of bone density."
The researchers are studying an autoimmune disease in
mice that models the human disease multiple sclerosis.
The mouse condition, called experimental autoimmune
encephalitis (EAE), is an inflammatory autoimmune disease
of the central nervous system (CNS). In both disorders,
the immune system attacks a protein called myelin.
Myelin is part of the CNS electrical system, said
Fathman, a professor of medicine (immunology and
rheumatology) and senior author of the research paper,
which appeared in the May Journal of Experimental
Medicine. "The myelin acts as an insulator of the
electrical impulses that travel through the nervous
system, delivering messages to and from the brain. If you
damage the myelin, you short out the nerve," Fathman
said. This interrupts nerve signals and creates a variety
of clinical problems ranging from double vision and
stumbling to severe motor dysfunction and death.
The researchers engineered a retrovirus, replacing
part of its normal genetic cargo with the instructions to
make a molecule called interleukin 4 (IL4), which turns
down the immune response. IL4 is one of many cytokines,
which Shaw describes as "hormone-like molecules used
for communication" within the immune system. The
investigators then coaxed the retrovirus to infect a line
of T cells that homes to the central nervous system - the
site of inflammation in EAE. The idea was to trick the T
cells into secreting a "shutdown" signal, IL4,
in the vicinity of the inflammatory site.
The investigators infected the cell line in the test
tube and then transferred the cells back into mice that
were on their way to acquiring EAE. As predicted, mice
with the IL4-secreting T cells took longer to become ill,
and had milder symptoms, than mice containing control T
cells that did not produce IL4.
Shaw said there are no technical barriers to applying
the technique to humans, but a few more mouse studies
will be needed before that happens.
The advantage of this method over the majority of
approaches taken to control autoimmune disease lies in
its ability to deliver a therapeutic molecule to a
particular location in the body, Shaw said. This approach
solves the major problem inherent to autoimmune disease
treatment: turning off the body's attack against its
normal cells while maintaining the ability to fend off
dangerous intruders. Although systemic administration of
chemicals such as IL4 is possible and staves off
autoimmune attacks, it also leaves the body susceptible
to infection by harmful bacteria and viruses.
The new method is not limited to treating EAE and,
potentially, multiple sclerosis. "You can imagine
applying this method to any inflammatory autoimmune
disease - diseases like rheumatoid arthritis and
diabetes," Shaw said. "In fact, you can also
imagine that it's applicable to other situations where
you might want to alter the immune response. It would be
very helpful to be able to heighten the immune response
against cancer cells, for example, and to interfere with
the immune attack of transplanted organs."
The researchers are now improving their new tool,
trying to develop ways to control production of the
therapeutic molecules within the body. "One worry is
what happens when the immune cells finish their work and
leave the site of inflammation," Shaw said.
"They might suppress healthy immune responses
elsewhere in the body. It would be helpful to have a T
cell that could traffic through the body and not secrete
anything until it encounters a signal at the inflammatory
site. Then, once the inflammation is resolved, the
stimulus would no longer be around and the cell would
stop producing its cytokine."
The technology for this already exists, Shaw said.
"It's just a matter of adapting it to our
system."
Shaw received a Multiple Sclerosis Society
postdoctoral fellowship to carry out this work. The
research is supported by a National Institutes of Health
grant to Fathman. SR
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