Researchers work toward
tolerance of transplant organs
Two Emory investigators studying the mechanisms of immunosuppression
in organ transplantation are growing closer to achieving true "immune
tolerance"-the ability of patients to accept donor organs and tolerate
them over the long term without the need to depend on immunosuppresive medicines.
The Nov. 22 issue of the British medical journal The Lancet describes
recent developments in the strategy developed last year by associate professors
of surgery Christian Larsen and Thomas Pearson. The two investigators were
able to stop rejection of transplanted organs in laboratory mice by simultaneously
blocking two important pathways that stimulate the action of T-cells, one
of the immune system's primary weapons in fighting off invading microorganisms
and transplanted tissues.
Larsen and Pearson used reagents that blocked molecule pairs present
on the surface of cells and important in the function of the immune system.
One pair provides a "second signal" necessary for T-cell activation,
while the other is important for B-cell, macrophage, endothelial cell and
T-cell activation, all of which are involved in immune defense. Larsen and
Pearson found if they treated mice to block these two signalling pathways
at the time of transplant, they could maintain grafts of transplanted tissue
for long periods of time without using any other immunosuppressive medicines.
Recently, researchers from the U.S. Naval Medical Research Institute
in Bethesda, Md., used the double-blocking therapy successfully in kidney
transplants in rhesus monkeys, who were still healthy six months after transplant
despite being given no immunosuppressive medications.
In the October 1997 issue of Current Opinion in Immunology, Larsen and
Pearson further describe the crucial role played by the pair CD40 and how
knowledge about the influence of this molecule promises to yield new therapeutic
agents that might ultimately produce human transplant tolerance. The CD40
pathway may help answer one of the most difficult questions of transplantation,
said Pearson: "Why can the immune response be suppressed or blocked
for a long while yet resurface much later to reject transplanted organs?
"In our studies of mice," he continued, "we found that
even though engrafted tissues were tolerated for much longer periods with
the double-blocking strategy, eventually the grafts were rejected."
After recent experiments combining other therapies with the blocking
mechanisms, however, Larsen and Pearson believe they may be close to achieving
true tolerance-"the golden ring the transplant community has been seeking
all along," Pearson said.
"Immunosuppression medicines, which patients must take as long as
they live, work well in the short term, where survival rates are really
good for heart, liver and kidney transplants," he noted, "but
the grafts continue to be lost in the long term. The other side of the coin
is that immunosuppression medicines are non-specific, so not only do they
block the immune response to the transplant but also to viral and bacterial
infections, and they may lead to complications such as diabetes, osteoporosis,
kidney failure and malignancies."
On the first of this year, the Carlos and Marguerite Mason Trust, which
has funded Larsen and Pearson's work since 1995, announced a new grant of
$1,465,000 to Emory for research projects aimed at developing a clincially
applicable tolerance induction strategy that would promote acceptance of
organ transplants without the need for long-term immunosuppression. Larsen
is principal investigator of the grant, which will reflect an ongoing collaboration
he and Pearson have with Fadi Lakkis and James Tumlin in the nephrology
division of the Department of Medicine.
The Emory researchers are hopeful that recently completed experiments
using the blocking strategy in organ or tissue transplants between animals
of different species will eventually help make trans-species transplants
available for humans, greatly increasing the number of available organs.
Currently, organs for transplant are in short supply, and almost 4,000
Americans a year die while waiting for a compatible donor.
to January 26, 1998 Contents Page