February 2004 - An experimental cross-species transplant to treat diabetes has passed an early test in rats with better-than-expected results, suggesting the innovative approach might halt type 1 diabetes while greatly reducing the risk of rejection.
Scientists at Washington University School of Medicine in St. Louis set up control and experimental groups of rats with diabetes. The experimental group received embryonic pig pancreas cell transplants and antirejection drugs to prevent the rats' immune systems from destroying the transplants. The control group received only the transplants and no immune suppression drugs. To the researchers' surprise, the control group's transplants grew unmolested by the immune system, halting the rats' diabetes and changing the focus of the study to transplanting without the need for immune suppression.
"Every once in a while you get lucky, and now we have the possibility of transplanting these pig cells and not having to worry about rejection," says Marc R. Hammerman, M.D., the Chromalloy Professor of Renal Diseases in medicine and leader of the study.
The results appear online and will be published in the April issue of The American Journal of Physiology-Endocrinology and Metabolism.
Hammerman, an endocrinologist and director of the Renal Division, is a leader in the emerging field of organogenesis, which is focused on growing organs from stem cells and other embryonic cell clusters known as organ primordia. Unlike stem cells, primordia cannot develop into any cell type -- they are locked into becoming a particular cell type or one of a particular set of cell types that make up an organ.
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In multiple groups of diabetic rats that were unable to produce their own rat insulin, Hammerman and Sharon Rogers, research instructor in medicine, transplanted pig pancreas primordia into the omentum, a membrane that envelops the intestines and other digestive organs. Within two weeks, the primordia engrafted and began producing pig insulin.
The pig insulin replaced the missing rat insulin, returning the rats' blood glucose to normal levels, an effect that continued for the rest of their lives. Failure to gain weight, another characteristic symptom of diabetes, was also reversed following the transplants.
In a final group of transplant recipients, Rogers, Hammerman, Feng Chen, Ph.D., assistant professor of medicine, and Mike Talcott, D.V.M., director of veterinary surgical services, showed that pig insulin-producing cells were present in the omentum and had caused a buildup of fat, a change previously linked to successful engraftment of pancreatic tissue.
Hammerman had theorized for years that implanting primordia obtained very soon after organ formation and coaxing the cells into growing into fully functioning organs inside a transplant recipient might reduce immune system rejection. However, he admits he is stunned by the new success.
"Conditions that are permissive for transplantation from one species to another frequently don't translate to transplants into another species," Hammerman says. "But this dramatic elimination of the need for immune suppression is quite unusual; there's not a lot of precedent in the literature for it. So it's possible that it may also apply in other cross-species transplants and maybe even in pig-to-human transplants."
Diabetes in humans is sometimes treated by transplanting human insulin-producing pancreas cells known as the islets of Langerhans. According to Hammerman, using embryonic pig cells as the transplant source instead of human islets circumvents three major difficulties.
"First, there aren't nearly enough human pancreas organs to go around," Hammerman says. "Since pig insulin works fine in humans, if pigs could be used as donors the shortage would be alleviated."
Second, islets can only be extracted from the pancreas by mincing the organ and exposing it to enzymes that break down connective tissue.
"This damages islets," Hammerman says. "So not all of the transplanted islets engraft, and many that do engraft die after a period of time."
Third, islets are composed of mature cells unable to respond to increased need for their services by dividing and producing more cells. In contrast, embryonic pancreas cells divide readily in response to such needs, resulting in a potentially expandable source of insulin.
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For reasons not yet understood, the transplanted pancreas cells did not develop an additional digestive function normally associated with the pancreas.
"That was another remarkably lucky break," Hammerman notes, "because only the endocrine cells are required to treat diabetes. The digestive cells would have only caused problems."
If elimination or reduction of immune rejection transfers to pig-to-human transplants, the technique will defeat or greatly diminish a final formidable obstacle to treating diabetes with transplants.
"Immunosuppressing a patient introduces a whole new set of dangers and side effects," says Hammerman. "Patients with type 1 diabetes have to ask themselves, would I rather take insulin, or would I rather take all these immunosuppressive drugs? It's not the greatest choice in the world."
The next phase of research will involve pig-to-primate transplants. If those are successful, then pig-to-human transplant trials can be considered.
Hammerman also is studying the use of kidney primordia from embryonic pigs to grow new kidneys inside recipients as a treatment for end-stage kidney failure.
Rogers SA, Chen F, Talcott M, Hammerman MR. Islet cell engraftment and control of diabetes in rats after transplantation of pig pancreatic anlagen. American Journal of Physiology-Endocrinology and Metabolism, April 2004.
Funding from the National Institutes of Diabetes and Digestive and Kidney Diseases supported this research.
Source: Washington University School of Medicine
