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Insight Into Transplant Rejection Might Lead to Novel Prevention Therapies

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Duke Health News 919-660-1306

ORLANDO, Fla. -- A newly discovered means by which the body
attacks transplanted organs might lead to novel methods of
preventing the rejection response, research by Duke University
Medical Center pulmonologists and transplant surgeons suggests.
The finding sheds new light on the role of the innate immune
system, the body's first line of defense, in the acute
rejection of transplanted lungs.

Drugs targeting the immune reaction could help combat early
lung rejection and its complications, thereby increasing
patients' chances of survival following the surgery, the
researchers said.

Lung transplant recipients with particular variants of a
gene called TLR4, which is critical in the lung's defense
against bacterial infection, were significantly less likely to
suffer acute rejection of the organs, the team found. The
researchers presented their results at the 100th International
Conference of the American Thoracic Society on May
24, 2004. The work was supported by the National Heart, Lung,
and Blood Institute, the National Institute of Environmental
Health Sciences, and the Department of Veteran Affairs.

"Those patients with particular variants of the innate
immune system gene have a sustained decrease in the frequency
and severity of rejection," said Scott Palmer, M.D., medical
director of the Duke University Medical Center Lung Transplant
Program and lead author of the study. "The finding is
consistent with the novel idea that innate immunity regulates
the rejection of transplanted lungs."

The innate immune system plays a critical role in combating
foreign invaders immediately after infection or exposure,
before the body's adaptive immune system can recognize the
invasion and launch its attack. While physicians have generally
attributed organ transplant rejection solely to the adaptive
immune system, the new work indicates an important role for the
body's first line of defense, Palmer said.

Acute rejection occurs in 60 percent of lung recipients
despite current immunosuppressive treatments, all of which are
directed at the adaptive immune system, he added. Although the
initial rejection can in many cases be managed with further
treatment, a new suite of drugs aimed at suppressing the innate
response in the lung could significantly improve patient
outcomes, Palmer said.

The researchers screened 200 transplant recipients and their
organ donors for the genetic makeup of TLR4, or "toll-like
receptor 4," a key component of innate immunity. Two variants
of the gene had earlier been linked to a reduced lung response
to bacterial toxins.

Recipients with a single copy of either of those two TLR4
variants exhibited a reduced rate of acute rejection during a
period of six months after surgery, the researchers found.
Specifically, acute rejection occurred in 28 percent of
recipients with the relevant TLR4 variants compared to 58
percent of recipients with more common forms of the gene. The
innate immunity genes of the donor had no effect on the chances
of rejection, they reported.

The long- and short-term survival of patients after lung
transplant lags behind that of other transplanted organs,
Palmer said. The new study suggests that the strong innate
immune response in the lung might help to explain that
difference, he added.

"Innate immunity is critical in the lungs because the organ
has to deal constantly with inhalational exposures, including
infectious agents and environmental toxins," Palmer said.
"Therefore, the lung has an incredible array of innate
defenses, including immune cells with receptors like TLR4 built
in to recognize and respond to foreign pathogens. Further
understanding their role in transplant should greatly enhance
physicians' ability to prevent and treat clinical
rejection."

The team will conduct additional studies to further
elucidate the interaction between the innate and adaptive
immune systems following organ transplantation.

Collaborators on the study included Lauranell Burch, Ph.D.,
Anil Trindade, R. Duane Davis, M.D., David Howell, M.D., Walter
Herczyk, Nancy Reinsmoen, Ph.D., and senior author, David A.
Schwartz, M.D., all of Duke University Medical Center.

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