Scientists Develop Improved Protocol for Islet Cell Transplantation
being developed to treat diabetes by transplanting islet cells could
be significantly advanced by using a newly engineered version of a molecule
that blocks the immune system's ability to reject transplanted tissues.
Transplant immunologists at Emory University School of Medicine were
able to significantly prolong the survival of transplanted islet cells
in rhesus monkeys by using this novel molecule, called LEA29Y, as part
of an anti-rejection drug regimen. The research will be published in
the journal Diabetes and was published in the online edition January
The Emory transplant immunologists
treated diabetic rhesus monkeys with purified islet cells along with
a drug regimen containing LEA29Y, a molecule that is a mutant of the
fusion protein CTLA4-Ig. Although CTLA4-Ig is a potent inhibitor of
T cell responses, scientists have questioned its long term ability to
block transplant rejection and have been working to improve it with
a substitute form.
Type I diabetes results from
the autoimmune destruction of the insulin-producing cells in the pancreas.
Although transplantation of a whole pancreas is used to treat diabetes
in which insulin injections are no longer effective, organ transplant
patients are required to take lifelong daily regimens of immunosuppressive
medicines. These medicines may have toxic side effects leading to cancer,
kidney failure, diabetes, and osteoporosis and leave patients highly
susceptible to viral and bacterial infections. The medicines also may
not completely block the immune response to the transplant, and about
30% of patients experience episodes of organ rejection, requiring hospitalization
and extra doses of immunosuppresants.
The Emory transplant team
led by Christian P. Larsen, M.D., D.Phil., and Thomas C. Pearson, M.D.,
D.Phil., have been developing a strategy to induce immune tolerance
to transplanted organs and tissues by modulating the immune system to
inhibit harmful rejection responses while keeping protective responses
"When we turn off immune
responses to a transplant," explains Dr. Larsen, "we run into a potential
problem of turning off the immune response to viruses or other infectious
agents. We need to be able to induce tolerance to the transplant while
preserving protective immunity in the long-term to viruses."
Strategies to block the immune
response have centered around the pathways required by the immune system's
T cells to reject invading microorganisms as well as transplanted tissues.
At least two immune-system signals are required for optimal T cell activation.
One of the signals is referred to as the co-stimulatory pathway.
Manipulation of the co-stimulatory
pathway involving the interaction between CD28 and B7 antigens prevents
T cells from getting the necessary "second signals," and has shown great
promise in experimental models of autoimmune diseases including diabetes,
multiple sclerosis and lupus, as well as in preventing organ transplant
Although CTLA4-Ig recently
has been used successfully in many experimental models of transplantation,
LEA29Y has been shown in preclinical studies to have even more potent
immunosupressive properties. The Emory scientists hypothesized that
the mutant molecule would provide a more effective strategy for islet
In the current experiment,
the scientists removed the pancreases from two groups of animals, then
treated them for diabetes by injecting purified islet cells into the
liver. The islet transplant recipients were than treated using two different
immunosuppresion regimens. The control group of animals received only
the base regimen of rapamycin plus anti-IL-2R mAb, while the experimental
group received the base regimen with the addition of LEA29Y.
The experimental group experienced
significantly prolonged islet survival. In four out of five animals
receiving the LEA29Y regimen the transplanted islets survived for the
duration of the treatment period, which was 150 days. In contrast, the
animals receiving only the base regimen quickly rejected the transplanted
islets at one week.
"We believe this new strategy
for blocking the T-cell co-stimulatory pathway holds great promise for
improving the treatment of diabetes," says Dr. Larsen. "These results
demonstrate significant protection from rejection and provide a strong
rationale for clinical trials to test these strategies in human islet
Emory participates in a nationwide
Collaborative Network for Clinical Research on Immune Tolerance funded
by the National Institutes of Health (NIH) and the Juvenile Diabetes
Research Foundation. The current research was done in collaboration
with and funded by the NIH and Bristol-Myers Squibb Pharmaceutical Research