Islet transplantation is currently being explored as a treatment for patients with type 1 diabetes. A hallmark in the """"""""Edmonton protocol"""""""" is repeated infusions of islets obtained from 2-4 donors. In order to establish islet transplantation as an accepted treatment modality, and make tolerance induction regimes applicable, it is essential that the donor: recipient ratio is brought down to 1:1. A conceivable strategy to achieve this goal is presented. The Nordic Network for clinical islet transplantation serves a population of 25 million people and involves eight participating transplant centers. Islet isolation is centralized and over 400 human pancreases have been processed. Quality control criteria for release of human islets for clinical transplantation have been defined. Each participating transplant center will annually transplant 5-10 patients, establishing the program as one of the largest in the world (in total 35-70 patients/year). The size of the program and the uniformity of all the steps involved, from organ retrieval and islet isolation to clinical transplantation and post operative management, will make it possible to perform well controlled clinical studies within the network. We have in a series of reports demonstrated that an adverse thrombotic and inflammatory reaction (IBMIR) is elicited when islets come in contact with ABO compatible blood: characterized by a rapid binding, and activation of platelets to the islet surface and activation of the coagulation and complement systems. Within 15 minutes leukocytes are found infiltrating the islets resulting in disruption of islet integrity and islet loss. The mechanisms triggering IBMIR in clinical islet transplantation have been defined and clinically applicable inhibitors identified. The application builds on the notion that IBMIR is induced as a consequence of the interplay between the transplanted islets and the innate immune system of the recipient. This intense inflammatory response is the result of a chain of events which is already induced in the islets of the donor and aggravated by handling of the pancreas from retrieval until the isolated islets successfully engraft in the recipient. The experimental studies proposed aim to develop novel techniques and agents to down-regulate the inflammatory response in isolated islets and to minimize the innate immune response in the recipient. The present proposal aims to translate these findings to clinical islet transplantation making it possible to stepwise develop a clinical applicable protocol enabling """"""""cure"""""""" of patients with type 1 diabetes with islets from only one human pancreas, retrieved from a donor fulfilling the standard criteria for kidney donation. The successful completion of the clinical studies proposed will form a foundation for subsequent clinical trials aiming for induction of immunological tolerance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI065192-04
Application #
7285976
Study Section
Special Emphasis Panel (ZDK1-GRB-N (O3))
Program Officer
Bridges, Nancy D
Project Start
2004-09-30
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
4
Fiscal Year
2007
Total Cost
$1,801,545
Indirect Cost
Name
Uppsala University
Department
Type
DUNS #
350582201
City
Uppsala
State
Country
Sweden
Zip Code
SE-75-1 05
Hering, Bernhard J; Bridges, Nancy D; Eggerman, Thomas L et al. (2017) Comment on Harlan. Islet Transplantation for Hypoglycemia Unawareness/Severe Hypoglycemia: Caveat Emptor. Diabetes Care 2016;39:1072-1074. Diabetes Care 40:e111-e112
Eriksson, Olof; Selvaraju, Ramkumar; Eich, Torsten et al. (2016) Positron Emission Tomography to Assess the Outcome of Intraportal Islet Transplantation. Diabetes 65:2482-9
Hodik, M; Skog, O; Lukinius, A et al. (2016) Enterovirus infection of human islets of Langerhans affects ?-cell function resulting in disintegrated islets, decreased glucose stimulated insulin secretion and loss of Golgi structure. BMJ Open Diabetes Res Care 4:e000179
Hering, Bernhard J; Clarke, William R; Bridges, Nancy D et al. (2016) Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia. Diabetes Care 39:1230-40
Vågesjö, Evelina; Christoffersson, Gustaf; Waldén, Tomas B et al. (2015) Immunological shielding by induced recruitment of regulatory T-lymphocytes delays rejection of islets transplanted in muscle. Cell Transplant 24:263-76
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
Danielsson, Angelika; Pontén, Fredrik; Fagerberg, Linn et al. (2014) The human pancreas proteome defined by transcriptomics and antibody-based profiling. PLoS One 9:e115421
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
Hansson, Sara F; Korsgren, Stella; Pontén, 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

Showing the most recent 10 out of 32 publications