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Mouse study yields clue to why liver is less prone to rejection, say Pitt researchers

University of Pittsburgh Medical Center

BOSTON, May 17 - Researchers from the University of Pittsburgh's Thomas E. Starzl Transplantation Institute believe they have identified a mechanism that may help to explain why the liver enjoys privileged immunological status over other organs, making it the least vulnerable to rejection when transplanted.

Playing a central role in this mechanism is the dendritic cell, known for its ability to identify and present antigens, or foreign substances, to other immune system cells that are programmed to destroy the antigen. When mature, dendritic cells signal T cells, the soldiers of the immune system, to attack a transplanted organ, for example. But dendritic cells that reside in the liver are relatively docile in nature. Why this is, according to the Pitt study, may be due to the fact that they express lower amounts of a certain molecule that serves as a switch for the maturation process.

Reporting in a plenary session at the American Transplant Congress, the joint scientific meeting of the American Society of Transplant Surgeons and the American Society of Transplantation, An de Creus, Ph.D., identified the key molecule as a Toll-like receptor known as TLR-4. Toll-like receptors are like night watchmen that look for suspicious activity characterized by unusual patterns of other molecules. TLR-4 is known to react to lipopolysaccharide (LPS), a component found in the cell wall of bacteria. Reacting to LPS sets in motion a cascade of immune events that begins with the rapid maturation of dendritic cells.

Because of the liver's position downstream from the intestines, dendritic cells there encounter large amounts of LPS as remnants of bacteria from the gut are carried by blood flowing through the liver's portal vein. But unlike dendritic cells found elsewhere, such as in the spleen, dendritic cells that reside in the liver express less TLR-4, making them more apathetic toward LPS, the researchers found in their studies of mice.

"With the liver constantly being exposed to LPS it must have a mechanism that prevents its immune cells from being activated all the time, and we believe the low expression of TLR-4 is in part responsible. The same thing is probably happening in the setting of transplantation," explained Dr. de Creus, a research associate working in the laboratory of Angus Thomson, Ph.D., D.Sc., professor of surgery and immunology at the Thomas E. Starzl Transplantation Institute and University of Pittsburgh School of Medicine.

"In humans, perhaps it would be possible to manipulate dendritic cells of the donor organ so that they express little or no TLR-4. In this way, we might be able to induce complete immune tolerance of the liver," she added.

According to the researchers, their data are the first to show how TLRs are expressed by liver dendritic cells.

"This work has important implications for understanding the liver's inherent tolerogenic potential. But we still don't have enough information to understand why it is easier to get liver transplant patients off anti-rejection drugs compared to recipients of other organs," said Dr. Thomson.

In a mouse model, researchers compared the expression of TLR-4 and other Toll-like receptors by liver dendritic cells to dendritic cells found in the spleen, an organ more immune active than the liver. Liver dendritic cells expressed more TLR-3 and lower amounts of TLR-4 and TLR-9 than those in the spleen. However, the lower expression of TLR-4 by the liver dendritic cells correlated with their reduced capacity to be stimulated by LPS and activate T cells to induce secretion of interferons, which signal other immune system cells. The liver dendritic cells were not entirely incapable of reacting to LPS, they just required higher concentrations of LPS to mature, reported Dr. de Creus.

For her work, ATC recognized Dr. de Creus with a Young Investigator's Award. Such an award is given to those under the age of 40 who submit a scientific abstract judged to be among the very best. The award provides the recipient with $1,000 to help defray the costs of attending the meeting.


NOTE TO EDITORS: Abstract #539, "Low Toll-Like Receptor 4 Expression on Liver Dendritic Cells Correlates with Reduced Capacity to Activate Allogeneic T cells in Response to Endotoxin," is being presented at 9 a.m. as part of the Basic Plenary Session I. To arrange interviews with Dr. de Creus, please call Lisa Rossi at 412-916-3315. The press room at the American Transplant Congress opens at 10 a.m., Sunday, May 16 and may be reached by calling 617-954-3034.

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