Timing eliminates immune rejection in transplants

University scientists have learned that a temporal “window of opportunity” was critical to their earlier successes in treating diabetic rats with embryonic pig tissues.

In experiments published in 2004, the researchers were surprised to find 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 study published online by Transplant Immunology, 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 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,” Hammerman said.

Hammerman and Rogers are leaders in the emerging field of organogenesis, which focuses on growing organs from stem cells and other embryonic cell clusters called organ primordia. Unlike stem cells, which can become virtually any cell type, primordia are locked into becoming a particular cell type or set of cell types that make up an organ.

In earlier studies, the team 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 envelops 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 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 said.

Superficially, there appears to be relatively little difference between pancreatic primordia from 28-day-old and 35-day-old pig embryos.

“Pig gestation is about 120 days, and it takes every bit of that time for the pancreas to fully develop,” Hammerman said.

“There is no pancreas before embryonic day 28, and the 35-day-old pancreas is still very early stage tissue.”

Based on additional experiments, Hammerman believes 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.

The team has shown that no part of the digestive components of the pancreas, which are not needed to treat diabetes, develops after transplantation.

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,” Hammerman said. “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.”

In collaboration with scientists at the University of Alabama-Birmingham, Hammerman’s team 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.