Abstract
BackgroundTransplantation 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 FindingsImplantation 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.ConclusionsThese 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.
Highlights
Diabetes mellitus is a severe and debilitating chronic disease that develops in nearly 5% of the world’s population [1,2]
In the present study we examined growth potential, functionality, and immunogenicity of pig embryonic pancreatic tissue harvested at different gestational ages
Fully immunocompetent diabetic mice grafted with the embryonic day 42 (E42) pig pancreatic tissue and treated with an immunosuppression protocol comprising CTLA4-Ig and anti–CD40 ligand 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
Summary
Diabetes mellitus is a severe and debilitating chronic disease that develops in nearly 5% of the world’s population [1,2]. Transplantation of an entire pancreas or pancreatic islets would potentially benefit millions of such patients [7,8,9,10,11,12,13]. 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. 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
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