Evaluation of strategies to predict and improve early graft survival in clinical islet transplantation

Transplantation of the islets of Langerhans as a treatment for type 1 diabetes (T1DM) is a procedure still under development. For the last decade it has been possible to obtain insulin independence by repeated infusions of islets. However, most patients must resume insulin therapy in 2-3 years. The side effects associated with today s immunosuppressive medication limit the procedure to patients with severe and frequent episodes of hypoglycemia or to T1DM patients who need immunosuppressive medication for other reasons, e.g. due to previous kidney transplantation. The efficacy and long term results of islet transplantation need to be improved for the treatment to be considered for also other categories of patients.

In this thesis a new technique, the two-layer method (TLM), to avoid hypoxic damage to the pancreas during the period of cold storage between donor operation and islet isolation was evaluated. PET/CT was introduced in a preclinical large animal model of islet transplantation and thereafter used to study the early post-transplantation phase of clinical islet transplantation. Finally, a new ratio, delta CP/GCr, was used to evaluate short term outcomes of repeated clinical islet transplantations.

No significant differences could be seen in islet isolation yield or islet transplantation outcomes using TLM compared to conventional cold storage. When utilizing PET/CT to monitor the transplantation of [18F]-FDG labeled islets, these were heterogeneously spread in the liver, with fractions of the graft found in hot spots . At least 25 % of the radioactivity contained within the islets was lost during the transplantation indicating significant early damage to the graft, possibly due to the instant blood mediated inflammatory reaction (IBMIR). Evaluating the clinical outcome of 110 transplantations, we showed that a large islet graft, a high stimulation index and short cold ischemia time (CIT) were factors that significantly improved clinical outcome. No correlation was found between initial renal graft function and the outcome of islet transplantation from the same donor.

This thesis has investigated areas where improvements must be made for islet transplantation to reach higher efficacy and become a treatment modality for more patients. The need for repeated islet infusions has made it difficult to study the effect of each islet preparation. Tools have here been introduced to facilitate this individual evaluation. Factors that predict the clinical outcome have been identified. Findings include the importance of CIT. New methods to preserve the pancreas before isolation are needed to improve outcome of both isolation and transplantation. A large fraction of islets implanted is lost during transplantation. The presented PET/CT technique may be used to further characterize early post-transplantation events and can become an important instrument in evaluation of new methods to enhance initial islet survival.

List of scientific papers

I. Caballero-Corbalán J, Eich T, Lundgren T, Foss A, Felldin M, Källen R, Salmela K, Tibell A, Tufveson G, Korsgren O, Brandhorst D (2007). "No beneficial effect of two-layer storage compared with UW-storage on human islet isolation and transplantation." Transplantation 84(7): 864-9
https://pubmed.ncbi.nlm.nih.gov/17984839

II. Eich T, Eriksson O, Sundin A, Estrada S, Brandhorst D, Brandhorst H, Langstrom B, Nilsson B, Korsgren O, Lundgren T (2007). "Positron emission tomography: a real-time tool to quantify early islet engraftment in a preclinical large animal model." Transplantation 84(7): 893-8
https://pubmed.ncbi.nlm.nih.gov/17984843

III. Eich T, Eriksson O, Lundgren T; Nordic Network for Clinical Islet Transplantation (2007). "Visualization of early engraftment in clinical islet transplantation by positron-emission tomography." N Engl J Med 356(26): 2754-5
https://pubmed.ncbi.nlm.nih.gov/17596618

IV. Eriksson O, Eich T, Sundin A, Tibell A, Tufveson G, Andersson H, Felldin M, Foss A, Kyllönen L, Långström B, Nilsson B, Korsgren O, Lundgren T (2009). "Positron emission tomography in clinical islet transplantation" American Journal of Transplantation 9: 2816-2824

V. Lundgren T, Friberg A, Andersson H, Felldin M, Jenssen T, Kyllönen L, Tufveson G, Nilsson B, Korsgren O, Tibell A (2010). "Can the outcome of clinical islet transplantations be predicted pretransplant?" (Manuscript)