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Failure of 'scout cells' may lead to cancer in transplant patients

A serious form of cancer that occurs in some transplant patients may arise because cells that normally serve as scouts for the immune system become weakened, a new study suggests.

The cancer is caused by Epstein-Barr virus (EBV), a herpesvirus that infects more than 90 percent of Americans but is ordinarily kept under control by the immune system. That control can be lost in people whose immune system is suppressed to prevent rejection of a transplanted organ.

The cancer, called post-transplant lymphoproliferative disorder (PTLD), arises only in some transplant patients, but doctors don't know why.

This study, led by Ohio State University scientists, begins to answer that question.

The findings are published in the August issue of the American Journal of Transplantation.

“We've identified a mechanism that may explain why some patients develop PTLD and others don't,” says study leader Anne M. VanBuskirk, assistant professor of surgery and an OSU Comprehensive Cancer Center researcher.

“If we can understand the mechanism, perhaps we can discover how to prevent this type of cancer in transplant patients.”

The incidence of this cancer varies according to the organ transplanted, occurring in 1 to 2 percent of kidney transplant patients and in up to 20 percent of bone marrow and lung transplant patients. The disease usually arises within six months to a year after transplantation, and it can have a 70- to 80-percent mortality rate.

The study by VanBuskirk and her colleagues examines two types of immune cells: cells that act as scouts – scientists call them antigen-presenting cells – and memory T cells.

Scout cells detect the presence of viruses and other invaders and alert the immune system to the infection. Memory T cells are immune cells that have fought an earlier infection and remain ready to respond quickly should that infection occur again.

Most people are infected by EBV early in life and the immune system brings it under control, although the virus remains hidden in some cells of the body. If the infection flares up again, scout cells alert the memory T cells, which rapidly proliferate and hunt down and kill any cells that contain growing virus or have become cancerous.

“If memory T cells are re-stimulated properly, they can kill the cancerous cells before PTLD develops,” VanBuskirk says. “But if that re-stimulation is weak or is blocked, not all of the cells are destroyed and cancer can develop. So it is critical that these two cell types work together effectively.”

The present study suggests that PTLD arises because the scout cells can only weakly activate the memory T cells and stop their activation by other cells.

VanBuskirk and her team believe this happens because an immune-system substance causes changes in the scout cells, inhibiting their ability to warn memory T cells about the virus. That substance is called transforming growth factor-beta (TGFb).

The researchers discovered this by exposing healthy human scout cells to TGFb. Next, they combined the scout cells with T cells and PTLD-like cancer cells.

The T cells that grew alongside the scout cells exposed to TGFb were significantly less able to kill the cancer cells than were the T cells growing with scout cells not exposed to TGFb.

In addition, when scout cells from both groups were combined, the TGFb-exposed cells were stronger and prevented the unexposed scout cells from re-stimulating the memory T cells.

The present study follows earlier research led by VanBuskirk that suggests why only some transplant patients develop PTLD and not others.

The earlier study, published in a February 2005 issue of the journal Blood, suggested that the balance in the body of TGFb and a second immune substance called interferon gamma (IFNg) might influence development of the cancer.

The study showed that some people have a normal genetic difference that causes them to have lower levels of IFNg in the body and others to have higher levels.

The researchers then injected white blood cells from each of the two groups of people into immune-deficient mice. All the people were healthy and tested positive for EBV.

They found that white blood cells from people who had the genetic difference for lower IFNg?levels were more likely to cause EBV-related cancer in the mice than cells from people with the genetic difference for higher IFNg levels. They also found that blocking TGFb prevented the EBV-related cancer.

“We hypothesize that the balance between IFNg?and TGFb is probably important in determining whether or not the cancer develops,” VanBuskirk says.

In the new study, for example, adding IFNg to TGFb prevented the scout cells from changing and allowed them to strongly re-stimulate the memory T cells.

“If our hypothesis proves to be true,” VanBuskirk says, “it may one day be possible to identify transplant patients who are at greater risk for PTLD and to develop new therapies that prevent or treat the disease.”

Funding from the National Cancer Institute, the National Institute of Allergy and Infectious Diseases and the Roche Organ Transplantation Research Foundation supported this research.

Darrell E. Ward | EurekAlert!
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