December 19, 2003
Broad Eradication of T Cells to Prevent Organ Rejection
Hampers Efforts to Induce Tolerance
(Philadelphia, PA) – More than 300,000 organ transplants
have been performed in the United States since 1988,
according to the United Network for Organ Sharing. But
an organ transplant, by its very nature, means introducing
a foreign body into a person, triggering the immune
system to attack the invader, which often results in
organ rejection. To prevent this, most transplant recipients
take powerful immunosuppressive drugs designed to dampen
their entire immune system. While this reduces the risk
of organ rejection, it also increases the risk of opportunistic
infection, cancer, cardiovascular disease, and diabetes.
For years, researchers have been working to find ways
to train the immune system to accept the transplanted
organ without suppressing the entire system, an approach
called tolerance. Now, researchers at the University
of Pennsylvania School of Medicine have discovered
that one popular experimental strategy to try to induce
immune tolerance—killing host T-cells non-specifically--may
not be as effective as once thought, throwing a cautionary
light on current practices. Their findings were published
in the November 30, 2003 online edition of Nature
Medicine and will appear in the journal’s
January 2004 print edition. Researchers at Penn and
other research facilities are now in the process of
identifying which T-cells to target for elimination.
“Tolerance refers to doing something to a patient
once or over a limited period of time that makes that
patient permanently accept a transplant,” says
Laurence A. Turka, M.D., senior researcher
on the paper and chief of the Renal-Electrolyte &
Hypertension Division of the University of Pennsylvania
School of Medicine. The approach can be compared to
a vaccine in reverse. While a vaccine is designed to
stimulate the immune system to recognize a foreign pathogen
and attack it quickly, tolerance is designed to acclimate
the immune system to a foreign pathogen (in this instance,
the transplanted organ), so it doesn’t attack
it.
Researchers try two primary approaches in their attempts
to induce tolerance. In one, they replace the recipient’s
immune system with the donor immune system via a bone-marrow
transplant. In the other, they attempt to inactivate
or destroy mature T cells, immune system cells that
orchestrate the body’s response to infections
or other pathogens.
Regarding the latter strategy, several laboratories,
including Dr. Turka’s, have shown previously in
mice that inactivating T cells may only work transiently,
and therefore it is necessary to kill the T cells which
would otherwise attack the transplant. Identifying and
eliminating those specific T cells is a difficult process,
however, prompting many researchers to simply destroy
most T cells. The problem with this approach is that
when the T cell supply is depleted the few remaining
cells not only divide vigorously, but, in the process,
develop characteristics that make them extremely resistant
to tolerance. Normally T cells divide infrequently.
Depletion stimulates division among the residual cells.
As a result, they develop a “memory-like”
function that causes further attack on the transplanted
organ.
These results, says Dr. Turka, “may make people
rethink strategies of inducing tolerance. We believe
very strongly that you need to get rid of the particular
T cells that react to the transplant. What we think
we’ve done now is say that not only do you need
to get rid of them, but you need to make sure you don’t
get rid of all the other T cells. You need to leave
enough reserves so they don’t start proliferating
wildly.”
Dr. Turka can be contacted at 215-898-1018 or turka@mail.med.upenn.edu
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