Ongoing research projects Experimental cell transplantation

Project 1: Establish a GMP facility for human islet isolation for clinical islet  transplantation at OUH.
The Cell Transplantation Research Group at OUH performed the first clinical islet transplantation in Norway in 2001 with human islets isolated at Uppsala islet isolation facility in Sweden. Since then several clinical trials have been performed and as a result of this program OUH is offering (from 2011) islet transplantation as a clinical cellular therapy option for selected patients with brittle diabetes. Although the treatment needs further refinement, Norway together with Sweden, France and Switzerland is one of very few countries worldwide that has introduced islet transplantation as standard treatment in selected patients. We have in collaboration with department of Cell Therapy at Radiumhospitalet (leader Prof. Gunnar Kvalheim) establish a large scale GMP isolation facility (the first in Norway) for human insulin producing islets to be used in clinical applications. All patients receiving ITX in Norway (and the Nordic countries) are registered in the Nordic Islet Network database (NICS). Full traceability of corresponding donors is included.

Project 2: Establishing improved non-diabetogenic immunosuppressive (IS) protocols in islet transplantation, able to induce immune tolerance.
In collaboration with Prof Stein Bergan research group, department of Biochemistry OUH.
A key factor for success in islet transplantation is said to be avoidance of steroids (Edmonton protocol). The Edmonton protocol consists of tacrolimus, rapamycin (sirolimus) and IL-2 receptor induction. Subsequently, almost all conducted trials have used this protocol for IS, although it is documented that tacrolimus induces de novo diabetes in up to 25 % of allotransplanted patients. In addition many experimental in vitro and in vivo studies of islets exposed to immunosuppressive drugs have shown negative effects on insulin secretion, in vivo function, beta cell proliferation and beta cell apoptosis. These reports support the importance of alternative immunosuppressive regimens for preventing long-term islet graft failure. We have used selected compounds such as cyclosporine A, tacrolimus, rapamycin, mycophenolate mofetil (MMF), and glucocortiod and tested these alone or in combination due to their relevance in clinical and experimental transplantation with special emphasis on their influence on insulin metabolism in human islets in vitro (manuscript submitted). In addition, we have investigated the intracellular concentration of the selected drug described above in human islets. We intend to further study the drug interaction and possible role of transport proteins (ABCB1 (pgp), ATPO1) as well as drug metabolisms (CYP3A4) in human islets (manuscript submitted).

Project 3: Study effects of new compounds on human beta cell mass and function by using a double islet transplantation model in mouse.
In collaboration with AstraZeneca AB research team, Sweden.
We have established a double islet transplantation model which enable us to investigate the impact of new compounds on the expansion of beta cell mass and improvement of function of human or mouse origin. We have used this model to investigate the effect of donor age on the function of human islets in vivo (manuscript submitted). We have then investigated the impact of exendin-4 (glucagon-like peptide-1 agonist) on human and mouse beta cell proliferation, cell death, mass, metabolic parameters and function (manuscript in preparation).

Project 4: The role of the NLRP3 inflamasome in type 1 diabetes and islet transplantation.
In collaboration with Dr. Arne Yndestad and Dr. Trine Ranheim, Institute for Internal Medicine OUH.
Recently publications indicate a role of the NLPR3 inflammasome in type 2 diabetes. The inflammasome is part of the innate immune system and bye assembling during activation the protein promote the maturation of the pro-inflammatory cytokines IL-1beta and IL-18. This project seeks to unravel the role of the NLRP3 inflammasome in islet transplantation. Pancreatic islets are susceptible to hypoxia-induced dysfunction. Central to the injurious effects of hypoxia in many cell types, is involvement of inflammasomes like NLRP3. The NLRP3-ASC inflammasome complex is involved in the activation of casapse-1, interleukin- (IL)-1β and IL-18 secretion, and has been implicated in type 2 diabetes. Whether hypoxia could activate NLRP3 in islets is not established. In this study, we wanted to investigate whether ablation of the NLRP3 complex (NLRP3-/- or ASC-/-) could alleviate the negative impact of hypoxia on islets (manuscript i preparation)

Project 5: Improved viability and function of islets after co-culture with human adipose derived mesenchymal stem cells preconditioned in hypoxia.
The transplantation of human islets has the promise to cure diabetes type 1. However, the treatment is limited by early graft loss. Mesenchymal stem cells (MSC) have been shown to improve function and viability of islets in vitro and the transplant outcome both after indirect and direct co-culture. Adipose tissue is an alternative source for MSC giving a higher yield and with less discomfort and risk for the donor than bone marrow. The adipose derived MSC (adMSC) has been shown to increase in the
release of cytokines when exposed to hypoxia (1% O2) compare to normoxia (21% O2) for 48 hrs. The effect of adMSCs preconditioned with hypoxia on islets are unknown. In this study we investigate the effects of adMSCs preconditioned with
hypoxia compare to normoixa on co-culturing with islet in vitro. 

Project 6: The anti-inflammatory characteristics of adipose derived mesenchymal stem cells from patients with diabetes type 1 compared to cells from non- diabetic patients
The purpose of this study is to gain knowledge of the potential differences in adipose derived MSCs from diabetic and non-diabetic patients. This will allow us to better design improved treatment protocols for alternative treatments for DM 1, with special focus on islet transplantation. The project protocol is under preparation. 

Publication list 2013 (only includes publications from main members):
1. Shi JH, Scholz H, Huitfeldt HS, Line PD. The effect of hepatic progenitor cells on experimental hepatocellular carcinoma in the regenerating liver. Scand J Gastroenterol. 2014 Jan;49(1):99-108.
2. Lekva T, Bollerslev, J, Sahraoui, A, Scholz, H, Boeyum, H, Evang, JA, Godang, K, Aukrust, Ueland, T. Thioredoxin interacting protein is a potential regulator of glucose and energy homeostasis in endogenous Cushing's syndrome. PLoS One. 2013 May
3. Sahraoui A, Jensen KK, Ueland T, Korsgren O, Foss A, Scholz H. Anakinra and tocilizumab enhance survival and function of human islets during culture: implications for clinical islet transplantation. Cell transplantation. 2013. Epub 2013/05/03.

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