May 16, 2005 -- Scientists at Washington University School of Medicine in St. Louis have learned that a temporal "window of opportunity" was critical to their earlier successes in treating diabetic rats with embryonic pig tissues.
In those experiments, published in 2004, researchers were surprised to find that they didn't have to give anti-rejection drugs to diabetic rats treated with embryonic pig cell transplants. They had expected rats that received no immune suppression would reject the transplants. Instead, the new tissues engrafted with little difficulty, curing the rats of their diabetes.
In a new study to be published in the September issue of Transplant Immunology and currently available online, senior investigator Marc R. Hammerman, M.D., the Chromalloy Professor of Renal Diseases in Medicine, presents evidence that he and colleague Sharon A. Rogers, research instructor in medicine, harvested the embryonic pig tissues at precisely the right point in their development.
"When we again harvested the transplant tissues 28 days after fertilization, it reproduced our earlier results, but if we moved the time of harvesting back to 35 days after fertilization, the rats rejected the pig tissues and continued to be diabetic," says Hammerman, who is an endocrinologist and director of the Renal Division at Barnes-Jewish Hospital.
Hammerman and Rogers are leaders in the emerging field of organogenesis, which focuses on growing organs from stem cells and other embryonic cell clusters known as organ primordia. Unlike embryonic stem cells, which can become virtually any cell type, primordia are locked into becoming a particular cell type or one of a particular set of cell types that make up an organ.
In their earlier studies, Hammerman and Rogers had shown that transplantation of pig pancreatic primordia into diabetic rats cures their diabetes permanently without the need for immune suppression. The pig primordia are transplanted into the omentum, a membrane that envelopes the intestines and other digestive organs. When the primordia mature, they replace the missing rat insulin with pig insulin, returning the rats' blood glucose to normal levels.
"The absence of a need for immune suppression after transplanting from one species to another was such an unexpected and encouraging discovery that we wanted to find out more about why that worked and under what conditions it is possible," Hammerman says.
Superficially, there appears to be relatively little difference between pancreatic primordia from 28-day-old and 35-day-old pig embryos. "To put this in perspective, pig gestation is about 120 days, and it takes every bit of that time for the pancreas to fully develop," Hammerman explains. "There is no pancreas before embryonic day 28, and 35-day-old pancreas is still very early-stage tissue."
Hammerman and Rogers have demonstrated that the pancreatic transplants aren't altering the rats' immune systems. They showed that rats with successful pancreatic transplants still reject a transplant of a different type of pig primordia, embryonic kidney tissue, if they are not given immune suppression drugs.
Prior research by other scientists into the immune system's interactions with transplants had suggested that a second unsuccessful organ transplant can "wake up" the immune system and lead it to reject an earlier successful transplant of a different organ. However, this didn't happen in the rats that rejected secondary kidney transplants.
To Hammerman, this suggests that the pancreatic primordia may be effectively invisible to the rat's immune system. He theorizes that this invisibility is a result of the unusual ways 28-day-old tissues differentiate after transplantation. He and Rogers have shown that no part of the digestive components of the pancreas, which are not needed to treat diabetes, develops after cross-species transplantation of such primordia.
Even the endocrine part of the pancreas, where insulin is made, is different.
"There are no structures similar to the islets of Langerhans, only individual endocrine cells engrafted in the omentum. This is a perfect place for them to release insulin where it will do the most good -- directly into a key blood vessel known as the portal vein," Hammerman explains.
In a collaboration with scientists at the University of Alabama-Birmingham, Hammerman has received funding from the Juvenile Diabetes Research Foundation to transplant pig pancreatic primordia into diabetic primates. If the pig-to-primate work is successful, he hopes to move on to human trials.
Rogers SA, Liapis H, Hammerman MR. Normalization of glucose post-transplantation of pig pancreatic anlagen into non-immunosuppressed rats depends on obtaining anlagen prior to embryonic day 35. Transplant Immunology, vol. 15, issue 1, Sept. 2005.
Funding from the Juvenile Diabetes Research Foundation supported this research.
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