Transplantation of embryonic pig pancreatic tissue as a source of insulin has been suggested for the cure of diabetes. However, previous limited clinical trials failed in their attempts to treat diabetic patients by transplantation of advanced gestational age porcine embryonic pancreas. In the present study we examined growth potential, functionality, and immunogenicity of pig embryonic pancreatic tissue harvested at different gestational ages.
Methods and Findings
Implantation of embryonic pig pancreatic tissues of different gestational ages in SCID mice reveals that embryonic day 42 (E42) pig pancreas can enable a massive growth of pig islets for prolonged periods and restore normoglycemia in diabetic mice. Furthermore, both direct and indirect T cell rejection responses to the xenogeneic tissue demonstrated that E42 tissue, in comparison to E56 or later embryonic tissues, exhibits markedly reduced immunogenicity. Finally, fully immunocompetent diabetic mice grafted with the E42 pig pancreatic tissue and treated with an immunosuppression protocol comprising CTLA4-Ig and anti–CD40 ligand (anti-CD40L) attained normal blood glucose levels, eliminating the need for insulin.
These results emphasize the importance of selecting embryonic tissue of the correct gestational age for optimal growth and function and for reduced immunogenicity, and provide a proof of principle for the therapeutic potential of E42 embryonic pig pancreatic tissue transplantation in diabetes.
Diabetes is a growing global health problem. By 2030, more than 300 million people around the world will have this chronic, incurable disorder, double the current number. In non-diabetic people, cells in the pancreas called beta cells release insulin, a hormone that controls the level of sugar (glucose) in the blood. In diabetics, blood-sugar levels become dangerously high either because the beta cells have been destroyed so no insulin is made (type 1 diabetes, 5%–10% of all cases) or because the cells that normally remove sugar from the blood have become insensitive to insulin (type 2 diabetes). In particularly severe cases of type 2 diabetes, the beta cells also stop releasing insulin. People with type 2 diabetes can usually control their blood-sugar levels through diet and exercise and by taking oral anti-diabetic drugs; people with type 1 diabetes or severe type 2 diabetes have to replace the missing insulin by injections. It is very important that diabetics keep their blood-sugar levels as normal as possible to minimize the disorder's serious long-term complications. These include kidney failure, blindness, nerve damage, and an increased risk of heart disease and strokes.
Why Was This Study Done?
While individuals with type 1 diabetes can control their blood-sugar levels pretty well by carefully monitoring their life style and injecting insulin, potentially better control and fewer long-term complications can be achieved by providing a new source of insulin-producing cells through transplantation of pancreatic tissue from a dead human donor. However, because there is not enough human pancreatic tissue to treat all the diabetics who could benefit from such transplants, researchers are investigating other sources of insulin-producing cells. One possibility is pig pancreatic tissue. Glucose control is very similar in pigs and humans, pig insulin injections have been used for years to control diabetes, and pigs are in plentiful supply. However, besides general concerns about xenotransplantation (that is, transplantation from a foreign species such as pigs into humans), early attempts to treat human diabetes by transplantation of pancreatic tissue taken from pig embryos at late stages of gestation were not successful. The researchers involved in this study had done earlier experiments that suggested that the age of the pig donor tissue influences how well transplantation into other species works. They therefore wanted to test whether pancreatic tissue from younger pig embryos might work better for pancreas transplants: they hoped that younger tissue would grow and integrate better with the surrounding host tissue. Additionally, a major concern with all transplantations is whether the transplanted cells or tissue will be recognized as foreign and as such destroyed by the host's immune system. Because tissue from younger embryos is generally less likely to trigger an immune reaction, the researchers hoped that pancreatic tissue from younger pig embryos would be less readily recognized as foreign by the human immune system.
What Did the Researchers Do and Find?
They started by transplanting pancreatic tissue from pig embryos of different ages into mice with defective immune systems. Tissue taken about a third of the way through gestation (that is, from embryos 42 or 56 days old) grew better than tissue taken earlier or later, secreted more pig insulin over extended periods of time, and was better at maintaining normal blood-sugar levels when the beta cells of the host mice were destroyed. The researchers then examined whether embryonic pig pancreatic tissue of different ages triggered an immune reaction by seeing how well it survived when human immune system cells were also transplanted into the mice. Tissue from 42-day-old embryos came out best in this test too, suggesting that there is little or no “direct” immune reaction by circulating immune cells against pancreatic tissue from this stage. Finally, the researchers transplanted pancreatic tissue of this age into diabetic mice with an intact immune system. These mice rejected the transplants (presumably through an “indirect” immune reaction), but that rejection could be overcome when the recipient mice were treated with drugs that suppressed the part of their immune system that is responsible for these indirect immune reactions. (Human patients who receive a transplant are usually treated with drugs that suppress direct and indirect immune reactions.) When the mice were kept on the drugs, the grafts survived in the long term, and the mice had normal blood-sugar levels once the graft was well established.
What Do These Findings Mean?
These results suggest that the exact age of embryonic pig pancreatic tissue influences how well the transplanted tissue grows and integrates into a host from a different species (in this case, the mouse) and how strong an immune reaction it triggers. Overall, these results support the notion that pig embryonic pancreas tissue could potentially be a source of tissue for transplantation into human patients with diabetes. The next steps in exploring this possibility are likely to involve experiments in monkeys to find out how much tissue should be implanted and where, and to check that the transplanted tissue remains functional in these animals. The ability of the 42-day-old embryonic tissue to avoid direct immune rejection also needs to be confirmed. And, ideally, the goal remains to find ways to avoid an immune reaction altogether, so that recipients of transplants do not need to be continually treated with drugs that suppress their immune system (which makes them more susceptible to infections and can have other side effects). Xenotransplantation has potential benefits and risks and remains controversial. Studies like this one and others that seek to better understand the risks and benefits are necessary to allow reasonable decisions to be made.
Please access these Web sites via the online version of this summary at
• MedlinePlus pages on
diabetes and on
• Information from the
Juvenile Diabetes Research Foundation International Description
• Wikipedia pages on
pancreas transplantation (note: Wikipedia is a free online encyclopedia that anyone can edit)
Pancreatic tissue from embryonic pigs co-transplanted with or without human immune cells into immune-deficient mice suggests that the embryonic stage of the pig donor affects the immunogenicity of the graft.