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Transplanted Pig Islets Reverse Diabetes in Monkeys

Update provided by JDRF
New York, NY, March 15, 2006 — Researchers at two JDRF islet transplant centers were able to reverse diabetes in monkeys by transplanting islet cells from pigs, providing encouragement to people with type 1 diabetes that therapies with an expandable supply of healthy islets may become available.

The milestone studies, conducted at the University of Minnesota and the Emory University School of Medicine in Atlanta, were reported in the journal Nature Medicine . They showed that a combination of immune-suppressing drugs allowed the transplanted pig islets to avoid rejection and survive for several months.

“These findings are important to our efforts to find a potentially unlimited source of islets,” said JDRF Scientific Program Manager Brian Flanagan, Ph.D. “The results are another step forward, but we need to refine the procedure and establish its safety before we can start putting pig islets into people with diabetes.”

The Challenge of Cross-Species Transplants
A problem with transplantation is that the number of people with diabetes far exceeds the required human islets donated each year. To address the shortfall, researchers have been investigating a range of alternative sources of insulin-producing cells, including animal islets. Pigs are an attractive option because they are relatively easy to breed, and their organs are similar to those of humans. But transplanting tissue between species is difficult.

In cross-species transplants (“xenotransplants”), the human immune system mounts a fierce attack, called “hyperacute rejection,” on living tissue from any animal except certain primates. That attack destroys the transplanted cells within hours. Triggering this response is alpha-Gal, a sugar molecule on the surface of most nonhuman animal cells.

In a surprising discovery, Bernhard Hering, M.D., and colleagues at the JDRF Center for Islet Transplantation at University of California, San Francisco/University of Minnesota, found that islet transplants between species do not trigger hyperacute rejection. Rather, the transplant recipient's immune response primarily resembles the rejection of a same-species transplant. This suggested to them that islet xenotransplants do not carry the hyperacute risk of xenotransplants involving other tissue and that they could prevent rejection of pig islets with the right mix of immunosuppressive drugs.

At the same time, the Minnesota scientists were trying to further reduce the risk of hyperacute rejection by minimizing alpha-Gal levels. They found that if they kept the islets in culture for a few days before the transplant, it destroyed most of the islets' vascular cells, where the alpha-Gal molecules are located.

With the alpha-Gal issue minimized, Dr. Hering's team was able to focus on the more conventional rejection threat, testing various immunosuppressive drug combinations. The researchers cultured islets from pigs and transplanted them into 12 diabetic monkeys. In some of the primates, the islets restored blood glucose control for more than 100 days. One group of monkeys did especially well under their drug cocktail, with all the animals surviving at least 68 days, and four out of five surviving 111 days or more.

Neonatal Islets
The Emory study, led by Christian Larsen, M.D., at the JDRF Center for Islet Cell Transplantation at Emory University, tested islets from neonatal pigs in diabetic monkeys. Because they are immature, neonatal islets are potentially more advantageous than islets from adult pigs, as they are first, more capable of multiplying and growing inside the recipient after the transplant, and second, less likely to trigger a damaging immune system response in the recipient.

Earlier research showed that that neonatal islets worked well when transplanted into mice and pigs. But monkeys, like humans, present additional challenges because they have a natural reaction against alpha-Gal.

The researchers transplanted neonatal pig islets into three groups of diabetic monkeys. The control group that did not receive immune-suppressing drugs rejected the pig islets within a few days.  A second group, which did receive immune suppression, regained control of blood glucose levels and survived much longer until succumbing to side effects of the drugs. The researchers subsequently transplanted a third group after refining the treatment with lessons learned from the second group. This last group survived for a median of more than 140 days.

The immune-suppressing cocktails used in both studies have significant hurdles for use in humans because of the side effects of the drugs. But the research clarified the mechanism of the primate immune response to transplanted pig tissue, which will help researchers as they design immune-suppressing therapies for future human transplant protocols.

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