| March 5, 2002
The Path to Chronic Transplant Rejection:
How Donor Organs Unwittingly Give Themselves Up to the
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
"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
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
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
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
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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.