Insight Into Transplant Rejection Might Lead To Novel Prevention Therapies

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.