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March 5, 2002

The Path to Chronic Transplant Rejection: How Donor Organs Unwittingly Give Themselves Up to the Immune System

(Philadelphia, PA) - Otherwise innocuous cells within donated tissue may be responsible for triggering the chronic rejection of transplanted organs, according to researchers at the University of Pennsylvania School of Medicine. Their findings, published in the March issue of Nature Medicine, represent a significant advance in the understanding of the mechanisms that trigger chronic rejection.

"These findings may have important implications for our understanding of chronic rejection, which targets blood vessels of the graft," said cardiothoracic surgeon Bruce R. Rosengard, MD, Surgical Director of the Heart-Lung Transplantation Program at the Hospital of the University of Pennsylvania. "Acute rejection is only the first hurdle for a heart transplant patient. The primary cause of late death is chronic rejection in the form of accelerated arteriosclerosis, and the risk of this lethal complication increases steadily through time."

Their studies have shown that donor endothelial cells, which are the cells that line blood vessels, activate the recipient's CD8+ "killer" T cells directly, a mechanism which was not previously thought to factor in the rejection response. Until now, the only known mechanism held that certain highly immunogenic white blood cells from the donor, carried within the transplant, migrate from the graft to the recipient's lymph nodes and spleen, where they elicit the rejection response, chiefly by activating CD4+ "helper" T cells.

Since these donor-derived "passenger" cells disappear over time, it has been believed that chronic rejection must be caused by a different mechanism.

"Transplanting tissue is like sneaking a dog into class: if your teacher doesn't notice immediately, it is only a matter of time before the barking gives it away," said Rosengard. "We have immunosuppressants that work fairly well to "muzzle" the immune system from reacting to the initial exposure to highly immunogenic passenger cells, thus preventing acute rejection. The newly reported experiments hypothesize that long-term survival may depend on keeping the blood vessels in the transplant itself from announcing the presence of the graft."

An immune response is dependent on the ability of lymphocytes, a subset of white blood cells, to recognize foreign cells or bits of foreign cells, called antigen. Acute rejection is thought to occur as CD4+ T cells interact with antigen in the recipient's lymphoid organs, sending an alarm that initiates a body-wide immune response. CD8+ T cells, however, have the ability to destroy foreign cells directly. Rosengard and his colleagues have been able to demonstrate that, even in the absence of CD4+ T cells and antigen presenting cells, CD8+ T cells can be directly activated by donor endothelial cells.

T cells are activated when they encounter one of many types of immunostimulatory blood-borne cells, whose role involves presenting antigen to the T cells. CD4+ T cells cause acute rejection when they encounter donor antigen-presenting cells that have tagged along with the transplanted organ. Currently, immunosuppressant strategies have focused on the interaction between CD4+ T cells and donor antigen-presenting cells, by either blocking the interaction or reducing the numbers of CD4+ T cells. These strategies do not, however, seem to work consistently in fighting chronic rejection.

"Unfortunately, the role of CD8+ T cells hasn't been looked at as closely," said Rosengard. "What we have done is to look at what could activate CD8+ T cells other than antigen-presenting cells."

According to the researchers, these experiments confirm their previous findings that graft endothelial cells serve as 'non-professional' antigen-presenting cells to CD8+ T cells. There is a steep price to pay for this freelancing, as the activated CD8+ T cells will immediately kill the endothelial cells or related graft tissue. Indeed, CD8+ T cell activation will occur for the life of the transplanted tissue. "These attacks by CD8+ T cells could go on constantly until they overwhelm the graft," said Rosengard.

There are still many questions that will have to be answered before Rosengard's findings will translate into a treatment to prevent chronic rejection.

"With further research, one hopes that this information can lead to new strategies to induce a lasting tolerance for donated tissue," said Rosengard. "An organ graft, any organ graft, is the operation of last resort and we would like to increase the odds that it will last."

Funding for this research was provided by grants from the National Institutes of Health, the American Heart Association, and through the generosity of Craig and Elaine Dobbin.


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Editor's Note: The University of Pennsylvania Health System is distinguished not only by its historical significance - first hospital (1751), first medical school (1765), first university teaching hospital (1874), first fully integrated academic health system (1993) - but by its position as a major player on the world stage of medicine in the 21st century. Committed to a three-part mission of education, research, and clinical excellence, UPHS has excelled in all three areas. Penn ranked second among all American medical schools that received funds from the National Institutes of Health, perhaps the single most important barometer of research strength.


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