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January 11, 2002


Emory Scientists Develop Improved Protocol for Islet Cell Transplantation

New strategies 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 4, 2002.

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 intact.

"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 rejection.

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 cell transplantation.

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 transplantation."

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 Institute.

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