At the time of transplantation, the isolated islets are allowed to embolize the liver after infusion in the portal vein, a procedure that is unique in the area of transplantation. Others and we have demonstrated in a series of reports that an injurious thrombotic/ inflammatory reaction is elicited when islets come in direct contact with ABO-compatible blood. This reaction is termed the instant blood-mediated inflammatory reaction (IBMIR) and is induced as a consequence of the interplay between inflammatory mediators such as tissue factor (TF) and MCP-1 expressed by isolated human Islets and the innate immune system of the recipient. In clinical islet transplantation, the IBMIR is triggered within minutes after islet Infusion Into the portal vein. PET/CT scans performed during clinical islet transplantation with FDG labeled islets show that almost 40% of the islets transplanted were lost within the first few minutes. Based on these studies we hypothesize that the relatively low efficiency of clinical Islet transplantation and the need for Islets from multiple donors in order to obtain normoglycemia is likely to be related to the intravascular transplantation procedure and Initiation of IBMIR, leading to i) initial loss of a large number of islets, and ii) impaired islet engraftment and long-term survival with entrapment by size restriction of islets in the vessel lumen. Consequently only a small fraction of the transplanted islets become functionally incorporated into the liver parenchyma. LMW-DS has in relevant in vitro and in vivo models been shown to: 1) prevent the innate injurious reaction (IBMIR)-induced by the transplanted islets in contact with blood, and 2) markedly stimulate and potentiate the positive biological effects of HGF on islet engraftment and survival after intraportal islet transplantation. An open single centre phase I dose-finding study of LMW-DS was conducted on 34 healthy volunteers. LMW-DS could safely be infused for a period of up to 5 to 6 hours without clinically significant side effects. No signs of increased risks of bleeding were found when infusing LMW-DS at doses that maintain APTT at 150 s for 6h and the pharmacokinetic data were favorable from a safety aspect. Importantly, the phase I trial confirmed in humans that LMW-DS is an extremely potent agent for inducing sustained and high levels of circulating HGF In blood with anticipated beneficial effects on islet survival and engraftment. CIT-01Is designed to test the hypothesis that LMW-DS markedly enhance the efficacy of clinical islet transplantation by reducing the number of islets lost during the first few hours after transplantation and by supporting their engraftment via !he release and potentiation of HGF. The study entails 72 subjects (IA and IAK) randomized to receive either LMW-DS or heparin at the time of islets transplantation. The Nordic Network for clinical islet transplantation provides experienced personnel and expertise in all areas relevant to efficiently conduct CIT-01 In a timely and cost efficient manner, e.g., during the last 12 months 40 islet preparations was released for clinical transplantation.
(provided by applicant): The focus of CIT-01 is to minimize islet loss in the immediate post-transplantation period and to augment islet engraftment. If so, a substantially larger mass would engraft and subsequent specific immune responses would be reduced making it possible to regularly cure patients with T1D with islets from only one donor. If successfully completed the proposed CIT-01 study would allow a widespread application of clinical islet transplantation and make the procedure attractive therapeutic option for people with T1D at an earlier stage before late complications have started to appear.
|Hansson, Sara F; Korsgren, Stella; Ponten, Fredrik et al. (2014) Detection of enterovirus in the islet cells of patients with type 1 diabetes: what do we learn from immunohistochemistry? Diabetologia 57:645-6|
|Nalin, Lovisa; Selvaraju, Ram K; Velikyan, Irina et al. (2014) Positron emission tomography imaging of the glucagon-like peptide-1 receptor in healthy and streptozotocin-induced diabetic pigs. Eur J Nucl Med Mol Imaging 41:1800-10|
|Moll, Guido; Hult, Annika; von Bahr, Lena et al. (2014) Do ABO blood group antigens hamper the therapeutic efficacy of mesenchymal stromal cells? PLoS One 9:e85040|
|Skog, Oskar; Ingvast, Sofie; Korsgren, Olle (2014) Evaluation of RT-PCR and immunohistochemistry as tools for detection of enterovirus in the human pancreas and islets of Langerhans. J Clin Virol 61:242-7|
|Selvaraju, Ram Kumar; Velikyan, Irina; Asplund, Veronika et al. (2014) Pre-clinical evaluation of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 for imaging of insulinoma. Nucl Med Biol 41:471-6|
|Moll, Guido; Alm, Jessica J; Davies, Lindsay C et al. (2014) Do cryopreserved mesenchymal stromal cells display impaired immunomodulatory and therapeutic properties? Stem Cells 32:2430-42|
|Hopfgarten, Johan; Stenwall, Per-Anton; Wiberg, Anna et al. (2014) Gene expression analysis of human islets in a subject at onset of type 1 diabetes. Acta Diabetol 51:199-204|
|Eriksson, Olof; Selvaraju, Ram K; Johansson, Lars et al. (2014) Quantitative imaging of serotonergic biosynthesis and degradation in the endocrine pancreas. J Nucl Med 55:460-5|
|Skog, Oskar; Korsgren, Stella; Melhus, Asa et al. (2013) Revisiting the notion of type 1 diabetes being a T-cell-mediated autoimmune disease. Curr Opin Endocrinol Diabetes Obes 20:118-23|
|Brandhorst, H; Iken, M; Scott 3rd, W E et al. (2013) Quality of isolated pig islets is improved using perfluorohexyloctane for pancreas storage in a split lobe model. Cell Transplant 22:1477-83|
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