Dept. of Internal Medicine III
University Hospital Carl Gustav Carus at the Technische Universität Dresden, Germany
The intra-adrenal islet transplantation model. Convergence of pancreatic islets with endocrine “helper cells”.
Undine Schubert1, Henning Morawietz1, Stefan R. Bornstein1, Barbara Ludwig1.
1Dept. of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
A major limiting factor for long-term survival and function of islet transplants is in regard to the inappropriate microenvironment after intraportal transplantation. We aim to evaluate the microenvironment of the adrenal as a potentially beneficial transplantation site that promotes beta cell engraftment, survival, proliferation and long-term function as the adrenal offers extensive vascularization, anti-apoptotic and pro-proliferative effects of various signaling molecules and a local anti-inflammatory and immunosuppressive microenvironment.
For in vitro analysis of islet viability, function and reactive oxygen species (ROS) a co-culture system of adrenal cells and pancreatic islets was established. Pancreatic islets and adrenal cells were isolated from Wistar rats and co-cultured using inserts for up to 7 days and sequentially assayed for viability, insulin secretion and reactive oxygen species (ROS). The co-culture setting did not significantly impact on islet viability, insulin content and secretion and there is evidence that oxidative stress is markedly reduced in the presence of adrenal cells.
For in vivo studies, Streptozotocin induced diabetic NuNu-mice were used as islet recipients. For islet transplantation, the adrenal was exteriorized via retroperitoneal incision and 300 islets were injected through the upper pole of the gland or the kidney. Animals showed a fast decrease in blood glucose levels within the first days after transplantation in both groups, at around 10 days the curves between adrenal and kidney site drifted apart in favor of the adrenal site. Regardless of the transplantation site, islets showed a well preserved morphology and intense insulin staining. The intra-adrenally engrafted islets show significantly higher vascularization compared to the kidney capsule control.
To prove our concept in a more clinically relevant system we established a large animal model. Therefore diabetic minipigs were transplanted with porcine islets into the adrenal gland and in comparison into the right liver lobe. Six weeks after transplantation c-peptide was detectible in both groups. The intra-adrenally engrafted islets show better integration into adrenal tissue and higher vascularization compared to liver control where islets stuck in the vessels. Adrenal function was not affected analyzed by ACTH-test.
The preliminary work underlined the feasibility of islet transplantation into the adrenal with first promising results on the restoration of normoglycemia. The results achieved could prove the beneficial effect of the adrenal microenvironment on islet engraftment and function in vitro and in vivo and elucidate the underlying mechanisms in regards to promoting islet revascularization and protection from oxidative stress.
These studies provide new insights into microenvironmental parameters that may benefit islet engraftment and survival. The use of “helper” cells could provide a potent supplementary factor. With adrenal cells providing both immunomodulatory and neovascularization signals, the co-transplantation with islets, e.g. within encapsulating devices, may prove to be highly beneficial.
15:30 - 17:00
|Modifying Islet Immunity - Adaptive, Innate, and Xenoimmunity||The intra-adrenal islet transplantation model. Convergence of pancreatic islets with endocrine “helper cells”.||Plenary Room 1|