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  • 1.
    Abadpour, Shadab
    et al.
    Oslo Univ Hosp, Sect Transplant Surg, Oslo, Norway.;Oslo Univ Hosp, Inst Surg Res, Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Göpel, Sven O.
    AstraZeneca R&D Gothenburg, Dept CVMD Biosci, Gothenburg, Sweden..
    Schive, Simen W.
    Oslo Univ Hosp, Sect Transplant Surg, Oslo, Norway.;Oslo Univ Hosp, Inst Surg Res, Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Foss, Aksel
    Oslo Univ Hosp, Sect Transplant Surg, Oslo, Norway.;Oslo Univ Hosp, Inst Surg Res, Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Scholz, Hanne
    Oslo Univ Hosp, Sect Transplant Surg, Oslo, Norway.;Oslo Univ Hosp, Inst Surg Res, Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Glial cell-line derived neurotrophic factor protects human islets from nutrient deprivation and endoplasmic reticulum stress induced apoptosis2017In: Scientific Reports, E-ISSN 2045-2322, Vol. 7, article id 1575Article in journal (Refereed)
    Abstract [en]

    One of the key limitations to successful human islet transplantation is loss of islets due to stress responses pre- and post-transplantation. Nutrient deprivation and ER stress have been identified as important mechanisms leading to apoptosis. Glial Cell-line Derived Neurotrophic Factor (GDNF) has recently been found to promote islet survival after isolation. However, whether GDNF could rescue human islets from nutrient deprivation and ER stress-mediated apoptosis is unknown. Herein, by mimicking those conditions in vitro, we have shown that GDNF significantly improved glucose stimulated insulin secretion, reduced apoptosis and proinsulin: insulin ratio in nutrient deprived human islets. Furthermore, GDNF alleviated thapsigargin-induced ER stress evidenced by reduced expressions of IRE1 alpha and BiP and consequently apoptosis. Importantly, this was associated with an increase in phosphorylation of PI3K/AKT and GSK3B signaling pathway. Transplantation of ER stressed human islets pre- treated with GDNF under kidney capsule of diabetic mice resulted in reduced expressions of IRE1 alpha and BiP in human islet grafts with improved grafts function shown by higher levels of human C-peptide post-transplantation. We suggest that GDNF has protective and anti-apoptotic effects on nutrient deprived and ER stress activated human islets and could play a significant role in rescuing human islets from stress responses.

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  • 2.
    Abadpour, Shadab
    et al.
    Oslo University Hospital, Oslo, Norway.
    Halvorsen, Bente
    Oslo University Hospital, Oslo, Norway.
    Sahraoui, Afaf
    University of Oslo, Oslo, Norway.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Aukrust, Pål
    Oslo University Hospital, Oslo, Norway.
    Scholz, Hanne
    Oslo University Hospital, Oslo, Norway.
    Interleukin-22 reverses human islet dysfunction and apoptosis triggered by hyperglycemia and LIGHT2018In: Journal of Molecular Endocrinology, ISSN 0952-5041, E-ISSN 1479-6813, Vol. 60, no 3, p. 171-183Article in journal (Refereed)
    Abstract [en]

    Interleukin (IL)-22 has recently been suggested as an anti-inflammatory cytokine that could protect the islet cells from inflammation- and glucose-induced toxicity. We have previously shown that the tumor necrosis factor family member, LIGHT can impair human islet function at least partly via pro-apoptotic effects. Herein, we aimed to investigate the protective role of IL-22 on human islets exposed to the combination of hyperglycemia and LIGHT. First, we found up-regulation of LIGHT receptors (LTβR and HVEM) in engrafted human islets exposed to hyperglycemia (>11 mM) for 17 days post transplantation by using a double islet transplantation mouse model as well as in human islets cultured with high glucose (HG) (20mM glucose) + LIGHT in vitro and this latter effect was attenuated by IL-22. The effect of HG + LIGHT impairing glucose stimulated insulin secretion was reversed by IL-22. The harmful effect of HG + LIGHT on human islet function seemed to involve enhanced endoplasmic reticulum stress evidenced by up-regulation of p-IRE1α and BiP, elevated secretion of pro-inflammatory cytokines (IL-6, IL-8, IP-10 and MCP-1) and the pro-coagulant mediator tissue factor (TF) release and apoptosis in human islets, whereas all these effects were at least partly reversed by IL-22. Our findings suggest that IL-22 could counteract the harmful effects of LIGHT/hyperglycemia on human islet cells and potentially support the strong protective effect of IL-22 on impaired islet function and survival.

  • 3.
    Abadpour, Shadab
    et al.
    Oslo Univ Hosp, Dept Transplant Med, Sognsvannsveien 20, Oslo 0027, Norway.;Oslo Univ Hosp, Inst Surg Res, Sognsvannsveien 20, Oslo 0027, Norway.;Univ Oslo, Inst Basic Med Sci, Ctr Excellence, Hybrid Technol Hub, Oslo, Norway..
    Tyrberg, Bjorn
    AstraZeneca, BioPharmaceut R&D, Res & Early Dev Cardiovasc Renal & Metab, Peppredsleden 1, Gothenburg 43183, Sweden..
    Schive, Simen W.
    Oslo Univ Hosp, Dept Transplant Med, Sognsvannsveien 20, Oslo 0027, Norway.;Oslo Univ Hosp, Inst Surg Res, Sognsvannsveien 20, Oslo 0027, Norway..
    Huldt, Charlotte Wennberg
    AstraZeneca, BioPharmaceut R&D, Res & Early Dev Cardiovasc Renal & Metab, Peppredsleden 1, Gothenburg 43183, Sweden..
    Gennemark, Peter
    AstraZeneca, BioPharmaceut R&D, Res & Early Dev Cardiovasc Renal & Metab, Peppredsleden 1, Gothenburg 43183, Sweden.;Univ Linköping, Dept Biomed Engn, Linköping, Sweden..
    Ryberg, Erik
    AstraZeneca, BioPharmaceut R&D, Res & Early Dev Cardiovasc Renal & Metab, Peppredsleden 1, Gothenburg 43183, Sweden..
    Ryden-Bergsten, Tina
    AstraZeneca, BioPharmaceut R&D, Res & Early Dev Cardiovasc Renal & Metab, Peppredsleden 1, Gothenburg 43183, Sweden..
    Smith, David M.
    AstraZeneca, BioPharmaceut R&D, Res & Early Dev Cardiovasc Renal & Metab, Peppredsleden 1, Gothenburg 43183, Sweden.;AstraZeneca, BioPharmaceut R&D, Discovery Sci, Hit Discovery, Cambridge, England..
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Skrtic, Stanko
    AstraZeneca, BioPharmaceut R&D, Res & Early Dev Cardiovasc Renal & Metab, Peppredsleden 1, Gothenburg 43183, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Med, Gothenburg, Sweden..
    Scholz, Hanne
    Oslo Univ Hosp, Dept Transplant Med, Sognsvannsveien 20, Oslo 0027, Norway.;Oslo Univ Hosp, Inst Surg Res, Sognsvannsveien 20, Oslo 0027, Norway.;Univ Oslo, Inst Basic Med Sci, Ctr Excellence, Hybrid Technol Hub, Oslo, Norway..
    Winzell, Maria Sorhede
    AstraZeneca, BioPharmaceut R&D, Res & Early Dev Cardiovasc Renal & Metab, Peppredsleden 1, Gothenburg 43183, Sweden..
    Inhibition of the prostaglandin D2-GPR44/DP2 axis improves human islet survival and function2020In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 63, no 7, p. 1355-1367Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis Inflammatory signals and increased prostaglandin synthesis play a role during the development of diabetes. The prostaglandin D-2 (PGD(2)) receptor, GPR44/DP2, is highly expressed in human islets and activation of the pathway results in impaired insulin secretion. The role of GPR44 activation on islet function and survival rate during chronic hyperglycaemic conditions is not known. In this study, we investigate GPR44 inhibition by using a selective GPR44 antagonist (AZ8154) in human islets both in vitro and in vivo in diabetic mice transplanted with human islets. Methods Human islets were exposed to PGD(2) or proinflammatory cytokines in vitro to investigate the effect of GPR44 inhibition on islet survival rate. In addition, the molecular mechanisms of GPR44 inhibition were investigated in human islets exposed to high concentrations of glucose (HG) and to IL-1 beta. For the in vivo part of the study, human islets were transplanted under the kidney capsule of immunodeficient diabetic mice and treated with 6, 60 or 100 mg/kg per day of a GPR44 antagonist starting from the transplantation day until day 4 (short-term study) or day 17 (long-term study) post transplantation. IVGTT was performed on mice at day 10 and day 15 post transplantation. After termination of the study, metabolic variables, circulating human proinflammatory cytokines, and hepatocyte growth factor (HGF) were analysed in the grafted human islets. Results PGD(2) or proinflammatory cytokines induced apoptosis in human islets whereas GPR44 inhibition reversed this effect. GPR44 inhibition antagonised the reduction in glucose-stimulated insulin secretion induced by HG and IL-1 beta in human islets. This was accompanied by activation of the Akt-glycogen synthase kinase 3 beta signalling pathway together with phosphorylation and inactivation of forkhead box O-1and upregulation of pancreatic and duodenal homeobox-1 and HGF. Administration of the GPR44 antagonist for up to 17 days to diabetic mice transplanted with a marginal number of human islets resulted in reduced fasting blood glucose and lower glucose excursions during IVGTT. Improved glucose regulation was supported by increased human C-peptide levels compared with the vehicle group at day 4 and throughout the treatment period. GPR44 inhibition reduced plasma levels of TNF-alpha and growth-regulated oncogene-alpha/chemokine (C-X-C motif) ligand 1 and increased the levels of HGF in human islets. Conclusions/interpretation Inhibition of GPR44 in human islets has the potential to improve islet function and survival rate under inflammatory and hyperglycaemic stress. This may have implications for better survival rate of islets following transplantation.

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  • 4.
    Anagandula, Mahesh
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Richardson, Sarah J.
    University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, UK.
    Oberste, M. Steven
    Centers for Disease Control and Prevention, Atlanta, Georgia.
    Sioofy-Khojine, Amir-Babak
    School of Medicine, University of Tampere, Tampere, Finland.
    Hyoty, Heikki
    School of Medicine, University of Tampere, Tampere, Finland ,Fimlab Ltd, Pirkanmaa Hospital District, Finland.
    Morgan, Noel G.
    University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, UK.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Frisk, Gun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Infection of Human Islets of Langerhans With Two Strains of Coxsackie B Virus Serotype 1: Assessment of Virus Replication, Degree of Cell Death and Induction of Genes Involved in the Innate Immunity Pathway2014In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 86, no 8, p. 1402-1411Article in journal (Refereed)
    Abstract [en]

    Type 1 diabetes mellitus is believed to be triggered, in part, by one or more environmental factors and human enteroviruses (HEVs) are among the candidates. Therefore, this study has examined whether two strains of HEV may differentially affect the induction of genes involved in pathways leading to the synthesis of islet hormones, chemokines and cytokines in isolated, highly purified, human islets. Isolated, purified human pancreatic islets were infected with strains of Coxsackievirus B1. Viral replication and the degree of CPE/islet dissociation were monitored. The expression of insulin, glucagon, CXCL10, TLR3, IF1H1, CCL5, OAS-1, IFN beta, and DDX58 was analyzed. Both strains replicated in islets but only one of strain caused rapid islet dissociation/CPE. Expression of the insulin gene was reduced during infection of islets with either viral strain but the gene encoding glucagon was unaffected. All genes analyzed which are involved in viral sensing and the development of innate immunity were induced by Coxsackie B viruses, with the notable exception of TLR3. There was no qualitative difference in the expression pattern between each strain but the magnitude of the response varied between donors. The lack of virus induced expression of TLR3, together with the differential regulation of IF1H1, OAS1 and IFN beta, (each of which has polymorphic variants influence the predisposition to type 1 diabetes), that might result in defective clearance of virus from islet cells. The reduced expression of the insulin gene and the unaffected expression of the gene encoding glucagon by Coxsackie B1 infection is consistent with the preferential beta-cell tropism of the virus.

  • 5.
    Asif, Sana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Sedigh, Amir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Nordström, Johan
    Department of Transplantation Surgery, Karolinska University Hospital, Stockholm, Sweden.
    Brandhorst, Heide
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Jorns, Carl
    Department of Transplantation Surgery, Karolinska University Hospital, Stockholm, Sweden.
    Lorant, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Magnusson, Peetra U.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nowak, Greg
    Department of Transplantation Surgery, Karolinska University Hospital, Stockholm, Sweden.
    Theisinger, Sonja
    Novaliq GmbH, Heidelberg, Germany.
    Hoeger, Simone
    Department of Nephrology, Endocrinology and Rheumatology, University Medical Center Mannheim, Mannheim, Germany.
    Wennberg, Lars
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Brandhorst, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Oxygen-charged HTK-F6H8 emulsion reduces ischemia: reperfusion injury in kidneys from brain-dead pigs2012In: Journal of Surgical Research, ISSN 0022-4804, E-ISSN 1095-8673, Vol. 178, no 2, p. 959-967Article in journal (Refereed)
    Abstract [en]

    Background:

    Prolonged cold ischemia is frequently associated with a greater risk of delayed graft function and enhanced graft failure. We hypothesized that media, combining a high oxygen-dissolving capacity with specific qualities of organ preservation solutions, would be more efficient in reducing immediate ischemia-reperfusion injury from organs stored long term compared with standard preservation media.

    Methods:

    Kidneys retrieved from brain-dead pigs were flushed using either cold histidine-tryptophan-ketoglutarate (HTK) or oxygen-precharged emulsion composed of 75% HTK and 25% perfluorohexyloctane. After 18 h of cold ischemia the kidneys were transplanted into allogeneic recipients and assessed for adenosine triphosphate content, morphology, and expression of genes related to hypoxia, environmental stress, inflammation, and apoptosis.

    Results:

    Compared with HTK-flushed kidneys, organs preserved using oxygen-precharged HTK-perfluorohexyloctane emulsion had increased elevated adenosine triphosphate content and a significantly lower gene expression of hypoxia inducible factor-1 alpha, vascular endothelial growth factor, interleukin-1 alpha, tumor necrosis factor-alpha, interferon-alpha, JNK-1, p38, cytochrome-c, Bax, caspase-8, and caspase-3 at all time points assessed. In contrast, the mRNA expression of Bcl-2 was significantly increased.

    Conclusions:

    The present study has demonstrated that in brain-dead pigs the perfusion of kidneys with oxygen-precharged HTK-perfluorohexyloctane emulsion results in significantly reduced inflammation, hypoxic injury, and apoptosis and cellular integrity and energy content are well maintained. Histologic examination revealed less tubular, vascular, and glomerular changes in the emulsion-perfused tissue compared with the HTK-perfused counterparts. The concept of perfusing organs with oxygen-precharged emulsion based on organ preservation media represents an efficient alternative for improved organ preservation.

  • 6.
    Asplund, Olof
    et al.
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden..
    Storm, Petter
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden.;Wallenberg Neurosci Ctr, Dept Expt Med Sci Dev & Regenerat Neurobiol, Lund, Sweden..
    Chandra, Vikash
    Univ Helsinki, Fac Med, Stem Cells & Metab Res Program, Helsinki, Finland..
    Hatem, Gad
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden..
    Ottosson-Laakso, Emilia
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden..
    Mansour-Aly, Dina
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden..
    Krus, Ulrika
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden..
    Ibrahim, Hazem
    Univ Helsinki, Fac Med, Stem Cells & Metab Res Program, Helsinki, Finland..
    Ahlqvist, Emma
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden..
    Tuomi, Tiinamaija
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden.;Helsinki Univ Hosp, Abdominal Ctr, Folkhalsan Res Ctr, Dept Endocrinol, Helsinki, Finland.;Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland..
    Renström, Erik
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden..
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. , Sweden.;Univ Gothenburg, Inst Biomed, Dept Clin Chem & Transfus Med, Gothenburg, Sweden..
    Wierup, Nils
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden..
    Ibberson, Mark
    SIB Swiss Inst Bioinformat, Vital IT Grp, Lausanne, Switzerland..
    Solimena, Michele
    Tech Univ Dresden, Paul Langerhans Inst Dresden, Munich Univ Hosp Carl Gustav Carus, Helmholtz Ctr, Dresden, Germany.;Tech Univ Dresden, Fac Med, Dresden, Germany.;German Ctr Diabet Res DZD, Munich, Germany.;Max Planck Inst Mol Cell Biol & Genet, MPI CBG, Dresden, Germany..
    Marchetti, Piero
    Univ Pisa, Cisanello Univ Hosp, Dept Clin & Expt Med, Pisa, Italy..
    Wollheim, Claes
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden.;Univ Geneva, Fac Med, Dept Cell Physiol & Metab, Geneva, Switzerland..
    Artner, Isabella
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden..
    Mulder, Hindrik
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden..
    Hansson, Ola
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden.;Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland..
    Otonkoski, Timo
    Univ Helsinki, Fac Med, Stem Cells & Metab Res Program, Helsinki, Finland.;Helsinki Univ Hosp, Childrens Hosp, Helsinki, Finland..
    Groop, Leif
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden.;Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland..
    Prasad, Rashmi B.
    Lund Univ, Clin Res Ctr, Dept Clin Sci, Malmö, Sweden.;Lund Univ Diabet Ctr LUDC, Lund, Sweden.;Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.;Lund Univ, Human Tissue Lab, Diabet Ctr, Lund, Sweden..
    Islet Gene View-a tool to facilitate islet research2022In: Life Science Alliance, E-ISSN 2575-1077, Vol. 5, no 12, article id e202201376Article in journal (Refereed)
    Abstract [en]

    Characterization of gene expression in pancreatic islets and its alteration in type 2 diabetes (T2D) are vital in understanding islet function and T2D pathogenesis. We leveraged RNA sequencing and genome-wide genotyping in islets from 188 donors to create the Islet Gene View (IGW) platform to make this information easily accessible to the scientific community. Expression data were related to islet phenotypes, diabetes status, other islet-expressed genes, islet hormone-encoding genes and for expression in insulin target tissues. The IGW web application produces output graphs for a particular gene of interest. In IGW, 284 differentially expressed genes (DEGs) were identified in T2D donor islets compared with controls. Forty percent of DEGs showed cell-type enrichment and a large proportion significantly co-expressed with islet hormone-encoding genes; glucagon (GCG, 56%), amylin (IAPP, 52%), insulin (INS, 44%), and somatostatin (SST, 24%). Inhibition of two DEGs, UNC5D and SERPINE2, impaired glucose-stimulated insulin secretion and impacted cell survival in a human beta-cell model. The exploratory use of IGW could help designing more comprehensive functional follow-up studies and serve to identify therapeutic targets in T2D.

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    FULLTEXT01
  • 7.
    Bader, Erik
    et al.
    Helmholtz Zentrum Munchen, Inst Diabet & Regenerat Res, D-85764 Neuherberg, Germany.;Helmholtz Zentrum Munchen, Inst Stem Cell Res, D-85764 Neuherberg, Germany.;Helmholtz Zentrum Munchen, Inst Epidemiol 2, D-85764 Neuherberg, Germany..
    Migliorini, Adriana
    Helmholtz Zentrum Munchen, Inst Diabet & Regenerat Res, D-85764 Neuherberg, Germany.;Helmholtz Zentrum Munchen, Inst Stem Cell Res, D-85764 Neuherberg, Germany..
    Gegg, Moritz
    Helmholtz Zentrum Munchen, Inst Diabet & Regenerat Res, D-85764 Neuherberg, Germany.;Helmholtz Zentrum Munchen, Inst Stem Cell Res, D-85764 Neuherberg, Germany..
    Moruzzi, Noah
    Helmholtz Zentrum Munchen, Inst Diabet & Regenerat Res, D-85764 Neuherberg, Germany.;Karolinska Univ Hosp, Dept Mol Med & Surg, SE-17176 Stockholm, Sweden..
    Gerdes, Jantje
    Helmholtz Zentrum Munchen, Inst Diabet & Regenerat Res, D-85764 Neuherberg, Germany..
    Roscioni, Sara S.
    Helmholtz Zentrum Munchen, Inst Diabet & Regenerat Res, D-85764 Neuherberg, Germany..
    Bakhti, Mostafa
    Helmholtz Zentrum Munchen, Inst Diabet & Regenerat Res, D-85764 Neuherberg, Germany..
    Brandl, Elisabeth
    Helmholtz Zentrum Munchen, Inst Diabet & Regenerat Res, D-85764 Neuherberg, Germany..
    Irmler, Martin
    German Ctr Diabet Res DZD, D-85764 Neuherberg, Germany.;Helmholtz Zentrum Munchen, Inst Expt Genet, D-85764 Neuherberg, Germany..
    Beckers, Johannes
    German Ctr Diabet Res DZD, D-85764 Neuherberg, Germany.;Helmholtz Zentrum Munchen, Inst Expt Genet, D-85764 Neuherberg, Germany.;Tech Univ Munich, Ismaninger Str 22, D-81675 Munich, Germany..
    Aichler, Michaela
    Helmholtz Zentrum Munchen, Res Unit Analyt Pathol, D-85764 Neuherberg, Germany..
    Feuchtinger, Annette
    Helmholtz Zentrum Munchen, Res Unit Analyt Pathol, D-85764 Neuherberg, Germany..
    Leitzinger, Christin
    Helmholtz Zentrum Munchen, Inst Mol Toxicol & Pharmacol, D-85764 Neuherberg, Germany..
    Zischka, Hans
    Helmholtz Zentrum Munchen, Inst Mol Toxicol & Pharmacol, D-85764 Neuherberg, Germany..
    Wang-Sattler, Rui
    Helmholtz Zentrum Munchen, Inst Epidemiol 2, D-85764 Neuherberg, Germany..
    Jastroch, Martin
    German Ctr Diabet Res DZD, D-85764 Neuherberg, Germany.;Helmholtz Zentrum Munchen, Inst Diabet & Obes, D-85764 Neuherberg, Germany..
    Tschoep, Matthias
    German Ctr Diabet Res DZD, D-85764 Neuherberg, Germany.;Helmholtz Zentrum Munchen, Inst Diabet & Obes, D-85764 Neuherberg, Germany..
    Machicao, Fausto
    German Ctr Diabet Res DZD, D-85764 Neuherberg, Germany.;Univ Tubingen, Helmholtz Zentrum Munchen, Inst Diabet Res & Metab Dis, D-72076 Tubingen, Germany..
    Staiger, Harald
    German Ctr Diabet Res DZD, D-85764 Neuherberg, Germany.;Univ Tubingen, Helmholtz Zentrum Munchen, Inst Diabet Res & Metab Dis, D-72076 Tubingen, Germany.;Univ Tubingen, Div Endocrinol Diabetol Vasc Dis Nephrol & Clin C, Dept Internal Med, D-72076 Tubingen, Germany..
    Haering, Hans-Ulrich
    German Ctr Diabet Res DZD, D-85764 Neuherberg, Germany.;Univ Tubingen, Helmholtz Zentrum Munchen, Inst Diabet Res & Metab Dis, D-72076 Tubingen, Germany.;Univ Tubingen, Div Endocrinol Diabetol Vasc Dis Nephrol & Clin C, Dept Internal Med, D-72076 Tubingen, Germany..
    Chmelova, Helena
    German Ctr Diabet Res DZD, D-85764 Neuherberg, Germany.;Tech Univ Dresden, Univ Clin Carl Gustav Carus, Helmholtz Zentrum Munchen, PLID, D-01307 Dresden, Germany.;Tech Univ Dresden, Fac Med, DFG Ctr Regenerat Therapies Dresden CRTD, D-01307 Dresden, Germany..
    Chouinard, Julie A.
    German Ctr Diabet Res DZD, D-85764 Neuherberg, Germany.;Tech Univ Dresden, Univ Clin Carl Gustav Carus, Helmholtz Zentrum Munchen, PLID, D-01307 Dresden, Germany.;Tech Univ Dresden, Fac Med, DFG Ctr Regenerat Therapies Dresden CRTD, D-01307 Dresden, Germany..
    Oskolkov, Nikolay
    Lund Univ, Ctr Diabet, Diabet & Endocrinol, S-20502 Malmo, Sweden..
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Speier, Stephan
    German Ctr Diabet Res DZD, D-85764 Neuherberg, Germany.;Tech Univ Dresden, Univ Clin Carl Gustav Carus, Helmholtz Zentrum Munchen, PLID, D-01307 Dresden, Germany.;Tech Univ Dresden, Fac Med, DFG Ctr Regenerat Therapies Dresden CRTD, D-01307 Dresden, Germany..
    Lickert, Heiko
    Helmholtz Zentrum Munchen, Inst Diabet & Regenerat Res, D-85764 Neuherberg, Germany.;Helmholtz Zentrum Munchen, Inst Stem Cell Res, D-85764 Neuherberg, Germany.;German Ctr Diabet Res DZD, D-85764 Neuherberg, Germany.;Tech Univ Munich, Ismaninger Str 22, D-81675 Munich, Germany..
    Identification of proliferative and mature beta-cells in the islets of Langerhans2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 535, no 7612, p. 430-+Article in journal (Refereed)
    Abstract [en]

    Insulin-dependent diabetes is a complex multifactorial disorder characterized by loss or dysfunction of beta-cells. Pancreatic beta-cells differ in size, glucose responsiveness, insulin secretion and precursor cell potential(1-5); understanding the mechanisms that underlie this functional heterogeneity might make it possible to develop new regenerative approaches. Here we show that Fltp (also known as Flattop and Cfap126), a Wnt/planar cell polarity (PCP) effector and reporter gene(6), acts as a marker gene that subdivides endocrine cells into two subpopulations and distinguishes proliferation-competent from mature beta-cells with distinct molecular, physiological and ultrastructural features. Genetic lineage tracing revealed that endocrine subpopulations from Fltp-negative and -positive lineages react differently to physiological and pathological changes. The expression of Fltp increases when endocrine cells cluster together to form polarized and mature 3D islet mini-organs(7-9). We show that 3D architecture and Wnt/PCP ligands are sufficient to trigger beta-cell maturation. By contrast, the Wnt/PCP effector Fltp is not necessary for beta-cell development, proliferation or maturation. We conclude that 3D architecture and Wnt/PCP signalling underlie functional beta-cell heterogeneity and induce beta-cell maturation. The identification of Fltp as a marker for endocrine subpopulations sheds light on the molecular underpinnings of islet cell heterogeneity and plasticity and might enable targeting of endocrine subpopulations for the regeneration of functional beta-cell mass in diabetic patients.

  • 8. Banerjee, Meenal
    et al.
    Virtanen, Ismo
    Palgi, Jaan
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Otonkoski, Timo
    Proliferation and plasticity of human beta cells on physiologically occurring laminin isoforms2012In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 355, no 1, p. 78-86Article in journal (Refereed)
    Abstract [en]

    We have previously characterized the molecular composition of human islet basement membranes and shown that human beta cells bind to laminin 511 (LM511) through integrin alpha 3 beta 1 and Lutheran glycoprotein. We have now investigated the impact of physical contact between cultured human beta cells and the laminin isoforms occurring in their natural niche. Human islet preparations derived from 15 donors were used, beta cells and duct cells were purified by magnetic sorting. Overall beta-cell proliferation was low or undetectable. However, in many experiments the only proliferating beta cells were detected in contact with the laminin isoforms that are found in the human islets in vivo (511 and 411). Purified ductal and beta cells underwent epithelial-mesenchymal transition (EMT). LM511 partially blocked this dedifferentiation of purified beta cells, and did not affect purified duct cells. Interactions with the surrounding basement membrane are important for the growth and function of human beta cells. However, only a very limited level of beta-cell proliferation can be induced by exogenous factors. LM511 may be a useful substrate for human beta-cell maintenance in vitro.

  • 9.
    Bartlett, Stephen T.
    et al.
    Univ Maryland, Sch Med, Dept Surg, Baltimore, MD 21201 USA..
    Markmann, James F.
    Massachusetts Gen Hosp, Div Transplantat, Boston, MA 02114 USA..
    Johnson, Paul
    Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hering, Bernhard J.
    Univ Minnesota, Dept Surg, Schulze Diabet Inst, Box 242 UMHC, Minneapolis, MN 55455 USA..
    Scharp, David
    Prodo Labs LLC, Irvine, CA USA.;Scharp Lacy Res Inst, Irvine, CA USA..
    Kay, Thomas W. H.
    St Vincents Hosp, St Vincents Inst Med Res, Dept Med, Fitzroy, Vic 3065, Australia.;Univ Melbourne, Melbourne, Vic 3010, Australia..
    Bromberg, Jonathan
    Massachusetts Gen Hosp, Div Transplantat, Boston, MA 02114 USA..
    Odorico, Jon S.
    Univ Wisconsin, Dept Surg, Sch Med & Publ Hlth, Div Transplantat, Madison, WI USA..
    Weir, Gordon C.
    Joslin Diabet Ctr, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Boston, MA USA..
    Bridges, Nancy
    NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA..
    Kandaswamy, Raja
    Univ Minnesota, Dept Surg, Schulze Diabet Inst, Box 242 UMHC, Minneapolis, MN 55455 USA..
    Stock, Peter
    Univ San Francisco, Med Ctr, Div Transplantat, San Francisco, CA 94117 USA..
    Friend, Peter
    Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Gotoh, Mitsukazu
    Fukushima Med Univ, Dept Surg, Fukushima, Japan..
    Cooper, David K. C.
    Univ Pittsburgh, Thomas E Starzl Transplantat Inst, Pittsburgh, PA USA..
    Park, Chung-Gyu
    Seoul Natl Univ, Coll Med, Dept Biomed Sci, Xenotransplantat Res Ctr,Dept Microbiol & Immunol, Seoul, South Korea..
    O'Connell, Phillip
    Univ Sydney, Westmead Hosp, Westmead Millennium Inst, Ctr Transplant & Renal Res, Westmead, NSW 2145, Australia..
    Stabler, Cherie
    Univ Miami, Sch Med, Diabet Res Inst, Coral Gables, FL 33124 USA..
    Matsumoto, Shinichi
    Natl Ctr Global Hlth & Med, Tokyo, Japan.;Otsuka Pharmaceut Factory Inc, Naruto, Japan..
    Ludwig, Barbara
    Tech Univ Dresden, Dept Med 3, D-01062 Dresden, Germany.;Tech Univ Dresden, Univ Clin Carl Gustav Carus, Helmholtz Ctr, Paul Langerhans Inst Dresden, Dresden, Germany.;DZD German Ctr Diabet Res, Dresden, Germany..
    Choudhary, Pratik
    Kings Coll London, Weston Educ Ctr, Diabet Res Grp, London WC2R 2LS, England..
    Kovatchev, Boris
    Univ Virginia, Ctr Diabet Technol, Charlottesville, VA USA..
    Rickels, Michael R.
    Univ Penn, Dept Med, Perelman Sch Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA..
    Sykes, Megan
    Coulmbia Univ, Med Ctr, Columbia Ctr Translat Immunol, New York, NY USA..
    Wood, Kathryn
    Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Kraemer, Kristy
    NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA..
    Hwa, Albert
    Juvenile Diabet Res Fdn, New York, NY USA..
    Stanley, Edward
    Murdoch Childrens Res Inst, Parkville, Vic, Australia.;Monash Univ, Melbourne, Vic 3004, Australia..
    Ricordi, Camillo
    Univ Miami, Sch Med, Diabet Res Inst, Coral Gables, FL 33124 USA..
    Zimmerman, Mark
    BetaLogics, Raritan, NJ USA..
    Greenstein, Julia
    Juvenile Diabet Res Fdn, Discovery Res, New York, NY USA..
    Montanya, Eduard
    Univ Barcelona, Hosp Univ Bellvitge, CIBERDEM, Bellvitge Biomed Res Inst IDIBELL, Barcelona, Spain..
    Otonkoski, Timo
    Univ Helsinki, Childrens Hosp, Helsinki, Finland.;Univ Helsinki, Biomedicum Stem Cell Ctr, Helsinki, Finland..
    Report from IPITA-TTS Opinion Leaders Meeting on the Future of beta-Cell Replacement2016In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 100, p. S1-S44Article in journal (Refereed)
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    fulltext
  • 10. Bennet, W
    et al.
    Björkland, Anna
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Sundberg, B
    Brandhorst, D
    Brendel, MD
    Richards, A
    White, DJ
    Nilsson, Bo
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Groth, CG
    Korsgren, Olle
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Expression of complement regulatory proteins on islets of Langerhans: a comparison between human islet and islets isolated from normal and hDAF transgenic pigs.2001In: Transplantation, Vol. 27, p. 312-Article in journal (Refereed)
  • 11. Bennet, W
    et al.
    Wundberg, B
    Elgue, Graciela
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Larsson, Rolf
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    A new in vitro model for the study of pig-to human vascular hyperacute rejection.2001In: Xentotransplantation, Vol. 8, p. 176-Article in journal (Refereed)
  • 12.
    Berg, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Olsson, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Frisk, Gun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Antiviral Treatment of Coxsackie B Virus Infection in Human Pancreatic Islets2007In: Antiviral Research, ISSN 0166-3542, E-ISSN 1872-9096, Vol. 74, no 1, p. 65-71Article in journal (Refereed)
    Abstract [en]

    Enterovirus infections of the pancreatic islets are believed to trigger or precipitate the near total destruction of β-cells that constitutes type 1 diabetes (T1D). This study investigated the ability of an anti-picornaviral compound, pleconaril, to block the replication of two β-cell tropic Coxsackie B4 virus (CBV-4) strains in isolated human islets. The two strains, VD2921 and V89 4557, with demonstrated abilities to cause non-lytic persistence or lytic infection, respectively, in islets, represented two different potential mechanisms behind virus-induced T1D. The virus replication in the islets was studied with and without addition of pleconaril. In addition, islet morphology was studied every day. To test the effects of pleconaril and/or DMSO on the β-cells’ insulin secretion, glucose perifusions were performed on treated and untreated islets. Virus titrations showed a clear reduction of the replication of both strains after pleconaril treatment. The VD2921 strain was inhibited to undetectable levels. The V89 4557 strain, however, showed an initial reduction of titers but virus titers then increased despite the addition of a second dose of pleconaril. This incomplete inhibition of viral replication suggested the existence of a resistant subtype within this strain. Pleconaril treatment reduced the β-cells’ insulin secretion in response to glucose stimulation in some experiments and induced slight morphological changes to the islets compared to untreated controls. In summary, pleconaril reduced the replication of the two β-cell tropic CBV-4 strains in human islets. However, genetic differences between these strains influenced the effectiveness of pleconaril treatment. This stresses the importance of using multiple viral strains in antiviral tests.

  • 13.
    Berglund, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Karlsson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Biglarnia, Ali-Reza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Lorant, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Carlsson, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Obtaining regulatory T cells from uraemic patients awaiting kidney transplantation for use in clinical trials2013In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 173, no 2, p. 310-322Article in journal (Refereed)
    Abstract [en]

    Adoptive transfer of regulatory T cells (Tregs) has been proposed for use as a cellular therapy to induce transplantation tolerance. Preclinical data are encouraging, and clinical trials with Treg therapy are anticipated. In this study, we investigate different strategies for the isolation and expansion of CD4+CD25highCD127low Tregs from uraemic patients. We use allogeneic dendritic cells (DCs) as feeder cells for the expansion and compare Treg preparations isolated by either fluorescence activated cell sorting (FACS) or magnetic activated cell sorting (MACS) that have been expanded subsequently with either mature or tolerogenic DCs. Expanded Treg preparations have been characterized by their purity, cytokine production and in-vitro suppressive ability. The results show that Treg preparations can be isolated from uraemic patients by both FACS and MACS. Also, the type of feeder cells used in the expansion affects both the purity and the functional properties of the Treg preparations. In particular, FACS-sorted Treg preparations expanded with mature DCs secrete more interleukin (IL)-10 and granzyme B than FACS-sorted Treg preparations expanded with tolerogenic DCs. This is a direct comparison between different isolation techniques and expansion protocols with Tregs from uraemic patients that may guide future efforts to produce clinical-grade Tregs for use in kidney transplantation.

  • 14.
    Berglund, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Karlsson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Palanisamy, Senthilkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Carlsson, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Imaging the in vivo fate of human T cells following transplantation in immunoincompetent mice - Implications for clinical cell therapy trials2013In: Transplant Immunology, ISSN 0966-3274, E-ISSN 1878-5492, Vol. 29, no 1-4, p. 105-108Article in journal (Refereed)
    Abstract [en]

    Many forms of adoptive T cell therapy are on the verge of being translated to the clinic. To gain further insight in their immunomodulating functions and to optimize future clinical trials it is essential to develop techniques to study their homing capacity. CD4+ T cells were labeled using [In-111]oxine, and the radioactive uptake was determined in vitro before intravenous injection in immunodeficient mice. In vivo biodistribution of [In-111] oxine-labeled cells or tracer alone was subsequently measured by mu SPECT/CT and organ distribution. CD4+ T cells incorporated [In-111]oxine with higher labeling yield using Ringer-Acetate compared to 0.9% NaCl. Cellular viability after labeling with [In-111]oxine was not compromised using less than 0.4 MBq/million cells. After intravenous infusion CD4+ T cells preferentially homed to the liver (p < 0.01) and spleen (p < 0.05). This study presents a protocol for labeling of T cells by [In-111]oxine with preserved viability and in vivo tracking by SPECT for up to 8 days, which can easily be translated to clinical cell therapy trials. 

  • 15.
    Berglund, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lorant, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Schneider, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Carlsson, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Isolation, expansion and functional assessment of CD4+CD25+FoxP3+ regulatory T cells and Tr1 cells from uremic patients awaiting kidney transplantation2012In: Transplant Immunology, ISSN 0966-3274, E-ISSN 1878-5492, Vol. 26, no 1, p. 27-33Article in journal (Refereed)
    Abstract [en]

    Background: The immunosuppressive properties of regulatory T cells have emerged as an attractive tool for the development of immunotherapies in various disease contexts, e.g. to treat transplantation induced immune reactions. This paper focuses on the process of obtaining and functionally characterizing CD4+CD25+FoxP3+ regulatory T cells and Tr1 cells from uremic patients awaiting kidney transplantation.

    Methods: From October 2010 to March 2011 uremic patients awaiting living donor kidney transplantation, and their corresponding kidney donors, were enrolled in the study. A total of seven pairs were included. Isolation of CD4+CD25+FoxP3+ regulatory T cells was performed by magnetic activated cell sorting of peripheral blood mononuclear cells obtained from the uremic patients. Donor specific Tr1 cells were differentiated by repetitive stimulation of immature CD4+ T cells with immature dendritic cells, with the T cells coming from the future kidney recipients and the dendritic cells from the corresponding kidney donors. Cells were then expanded and functionally characterized by the one-way mixed leukocyte reaction and assessment of IL-10 production. Phenotypic analysis was performed by flow cytometry.

    Results: The fraction of CD4+CD25+FoxP3+ regulatory T cells after expansion varied from 39.1 to 50.4% and the cells retained their ability to substantially suppress the mixed leukocyte reaction in all but one patient (3.8–19.2% of the baseline stimulated leukocyte activity, p<0.05). Tr1 cells were successfully differentiated from all but one patient and produced high levels of IL-10 when stimulated with immature dendritic cells (1,275–11,038% of the baseline IL-10 secretion, pb0.05).

    Conclusion: It is practically feasible to obtain and subsequently expand CD4+CD25+FoxP3+ regulatory T cells and Tr1 cells from uremic patients without loss of function as assessed by in vitro analyses. This forms a base for adoptive regulatory T cell therapy in the setting of living donor kidney transplantation.

  • 16.
    Bergström, Marcus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Müller, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Karlsson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Scholz, Hanne
    Oslo Univ Hosp, Dept Transplant Med, Oslo, Norway;Oslo Univ Hosp, Inst Surg Res, Oslo, Norway;Univ Oslo, Ctr Excellence, Inst Basic Med Sci, Hybrid Technol Hub, Oslo, Norway.
    Vethe, Nils Tore
    Oslo Univ Hosp, Dept Pharmacol, Oslo, Norway.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Comparing the Effects of the mTOR Inhibitors Azithromycin and Rapamycin on In Vitro Expanded Regulatory T Cells2019In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 28, no 12, p. 1603-1613Article in journal (Refereed)
    Abstract [en]

    Adoptive transfer of autologous polyclonal regulatory T cells (Tregs) is a promising option for reducing graft rejection in allogeneic transplantation. To gain therapeutic levels of Tregs there is a need to expand obtained cells ex vivo, usually in the presence of the mTOR inhibitor Rapamycin due to its ability to suppress proliferation of non-Treg T cells, thus promoting a purer Treg yield. Azithromycin is a bacteriostatic macrolide with mTOR inhibitory activity that has been shown to exert immunomodulatory effects on several types of immune cells. In this study we investigated the effects of Azithromycin, compared with Rapamycin, on Treg phenotype, growth, and function when expanding bulk, naive, and memory Tregs. Furthermore, the intracellular concentration of Rapamycin in CD4+ T cells as well as in the culture medium was measured for up to 48 h after supplemented. Treg phenotype was assessed by flow cytometry and Treg function was measured as inhibition of responder T-cell expansion in a suppression assay. The concentration of Rapamycin was quantified with liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Azithromycin and Rapamycin both promoted a FoxP3-positive Treg phenotype in bulk Tregs, while Rapamycin also increased FoxP3 and FoxP3+Helios positivity in naive and memory Tregs. Furthermore, Rapamycin inhibited the expansion of naive Tregs, but also increased their suppressive effect. Rapamycin was quickly degraded in 37 degrees C medium, yet was retained intracellularly. While both compounds may benefit expansion of FoxP3+ Tregs in vitro, further studies elucidating the effects of Azithromycin treatment on Tregs are needed to determine its potential use.

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  • 17.
    Bergström, Marcus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Rudbeck Laboratory Department of Immunology, Genetics and Pathology Section of Clinical Immunology Uppsala University Uppsala Sweden.
    Yao, Ming
    Division of Transplantation Surgery Department of Clinical Science, Intervention and Technology Karolinska Institute Stockholm Sweden;Department of Transplantation Surgery Karolinska University Hospital Stockholm Sweden.
    Müller, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Rudbeck Laboratory Department of Immunology, Genetics and Pathology Section of Clinical Immunology Uppsala University Uppsala Sweden.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    von Zur-Mühlen, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Lundgren, Torbjörn
    Division of Transplantation Surgery Department of Clinical Science, Intervention and Technology Karolinska Institute Stockholm Sweden;Department of Transplantation Surgery Karolinska University Hospital Stockholm Sweden.
    Autologous regulatory T cells in clinical intraportal allogenic pancreatic islet transplantation2021In: Transplant International, ISSN 0934-0874, E-ISSN 1432-2277, Vol. 34, no 12, p. 2816-2823Article in journal (Refereed)
    Abstract [en]

    Allogeneic islet transplantation in type 1 diabetes requires lifelong immunosuppression to prevent graft rejection. This medication can cause adverse effects and increases the susceptibility for infections and malignancies. Adoptive therapies with regulatory T cells (Tregs) have shown promise in reducing the need for immunosuppression in human transplantation settings but have previously not been evaluated in islet transplantation. In this study, five patients with type 1 diabetes undergoing intraportal allogeneic islet transplantation were co-infused with polyclonal autologous Tregs under a standard immunosuppressive regimen. Patients underwent leaukapheresis from which Tregs were purified by magnetic-activated cell sorting (MACS) and cryopreserved until transplantation. Dose ranges of 0.14–1.27 × 106 T cells per kilo bodyweight were transplanted. No negative effects were seen related to the Treg infusion, regardless of cell dose. Only minor complications related to the immunosuppressive drugs were reported. This first-in-man study of autologous Treg infusion in allogenic pancreatic islet transplantation shows that the treatment is safe and feasible. Based on these results, future efficacy studies will be developed under the label of advanced therapeutic medical products (ATMP), using modified or expanded Tregs with the aim of minimizing the need for chronic immunosuppressive medication in islet transplantation.

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    fulltext
  • 18.
    Biglarnia, Ali-Reza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Bennet, William
    Nilsson, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Magnusson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Yamamoto, Shinji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Lorant, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Sedigh, Amir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    von Zur-Mühlen, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Bäckman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Utilization of Small Pediatric Donors Including Infants for Pancreas and Kidney Transplantation: Exemplification of the Surgical Technique and the Surveillance2014In: Annals of Surgery, ISSN 0003-4932, E-ISSN 1528-1140, Vol. 260, no 2, p. e5-7Article in journal (Refereed)
  • 19.
    Brandhorst, Daniel
    et al.
    Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.;Churchill Hosp, OCDEM, Oxford, England..
    Parnaud, Geraldine
    Geneva Univ Hosp, Dept Surg, Cell Isolat & Transplantat Ctr, Geneva, Switzerland..
    Friberg, Andrew
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lavallard, Vanessa
    Geneva Univ Hosp, Dept Surg, Cell Isolat & Transplantat Ctr, Geneva, Switzerland..
    Demuylder-Mischler, Sandrine
    Geneva Univ Hosp, Dept Surg, Cell Isolat & Transplantat Ctr, Geneva, Switzerland..
    Hughes, Stephen
    Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.;Churchill Hosp, OCDEM, Oxford, England..
    Saphoerster, Julia
    SERVA Electrophoresis GmbH, Uetersen, Germany..
    Kurfuerst, Manfred
    SERVA Electrophoresis GmbH, Uetersen, Germany..
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Berney, Thierry
    Geneva Univ Hosp, Dept Surg, Cell Isolat & Transplantat Ctr, Geneva, Switzerland..
    Johnson, Paul R. V.
    Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.;Churchill Hosp, OCDEM, Oxford, England..
    Multicenter Assessment of Animal-free Collagenase AF-1 for Human Islet Isolation2017In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 26, no 10, p. 1688-1693Article in journal (Refereed)
    Abstract [en]

    Animal-free (AF) SERVA Collagenase AF-1 and Neutral Protease (NP) AF GMP Grade have recently become available for human islet isolation. This report describes the initial experiences of 3 different islet transplant centers. Thirty-four human pancreases were digested using 1 vial of the 6 different lots of Collagenase AF-1 (2,000-2,583 PZ-U/vial) supplemented with 4 different lots of NP AF in a range of 50 to 160 DMC-U per pancreas. Isolation, culture, and quality assessment were performed using standard techniques as previously described. All data are presented as mean +/- standard error of the mean (SEM). Variability of pancreas weight was associated with a wide range of collagenase and NP activities, ranging from 12.7 to 46.6 PZ-U/g (26.0 +/- 1.5 PZ-U/g) and 0.4 to 3.0 DMC-U/g (1.5 +/- 0.1 DMC-U/g), respectively. Postpurification islet yield was 296,494 +/- 33,620 islet equivalents (IEQ) equivalent to 3,274 +/- 450 IEQ/g with a purity of 55.9% +/- 3.2%. Quality assessment performed after 2 to 4 d of culture demonstrated a viability of 88.1% +/- 1.5% and a stimulation index of 3.7 +/- 0.7. Eighteen of the 34 preparations were transplanted into type 1 diabetic patients equivalent to a transplantation rate of 52.9%. Six preparations, which were infused into patients as first transplant, could be analyzed and increased the fasting C-peptide level from 0.11 +/- 0.08 pretransplant to 1.23 +/- 0.24 and 2.27 +/- 0.31 ng/mL 3 and 6 mo posttransplant (P < 0.05), respectively. Insulin requirements were simultaneously reduced at the same time from 39.2 +/- 3.8 IU/d before transplantation to 10.8 +/- 4.1 and 4.0 +/- 2.3 IU/d, after 3 and 6 mo posttransplant (P < 0.05), respectively. This study demonstrates the efficiency of AF SERVA Collagenase AF-1 and NP AF for clinical islet isolation and transplantation. The new plant-based production process makes these products a safe new option for the islet field.

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  • 20.
    Brandhorst, H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Iken, M.
    Scott, W. E. , I I I
    Papas, K. K.
    Theisinger, B.
    Johnson, P. R.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Brandhorst, D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Quality of Isolated Pig Islets Is Improved Using Perfluorohexyloctane for Pancreas Storage in a Split Lobe Model2013In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 22, no 8, p. 1477-1483Article in journal (Refereed)
    Abstract [en]

    Pancreas transportation between donor center and islet production facility is frequently associated with prolonged ischemia impairing islet isolation and transplantation outcomes. It is foreseeable that shipment of pig pancreases from distant centralized biosecure breeding facilities to institutes that have a long-term experience in porcine islet isolation is essentially required in future clinical islet xenotransplantation. Previously, we demonstrated that perfluorohexyloctan (F6H8) is significantly more efficient to protect rat and human pancreata from ischemically induced damage compared to perfluorodecalin (PFD). To evaluate the effect of F6H8 on long-term stored pig pancreases in a prospective study, we utilized the split lobe model to minimize donor variability. Retrieved pancreases were dissected into the connecting and splenic lobe, intraductally flushed with UW solution and immersed alternately in either preoxygenated F6H8 or PFD for 8-10 h. Prior to pancreas digestion, the intrapancreatic pO(2) and the ratio of ATP-to-inorganic phosphate was compared utilizing P-31-NMR spectroscopy. Isolated islets were cultured for 2-3 days at 37 degrees C and subjected to quality assessment. Pancreatic lobes stored in preoxygenated F6H8 had a significantly higher intrapancreatic pO(2) compared to pancreata in oxygen-precharged PFD (10.11 +/- 3.87 vs. 1.64 +/- 1.13 mmHg, p < 0.05). This correlated with a higher ATP-to-inorganic phosphate ratio (0.30 +/- 0.04 vs. 0.14 +/- 0.01). No effect was observed concerning yield and purity of freshly isolated islets. Nevertheless, a significantly improved glucose-stimulated insulin response, increased viability and postculture survival (57.2 +/- 5.7 vs. 39.3 +/- 6.4%, p < 0.01) was measured in islets isolated from F6H8-preserved pancreata. The present data suggest that F6H8 does not increase islet yield but improves quality of pig islets isolated after prolonged cold ischemia.

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  • 21.
    Brandhorst, Heide
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Asif, Sana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Andersson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Moench, Johanna
    Serva Electrophoresis GmbH, Uetersen, Germany..
    Friedrich, Olaf
    Nordmark Arzneimittel GmbH & Co KG, Uetersen, Germany..
    Raemsch-Guenther, Nicole
    Serva Electrophoresis GmbH, Uetersen, Germany..
    Raemsch, Christian
    Nordmark Arzneimittel GmbH & Co KG, Uetersen, Germany..
    Steffens, Melanie
    Serva Electrophoresis GmbH, Uetersen, Germany..
    Lambrecht, Joerg
    Nordmark Arzneimittel GmbH & Co KG, Uetersen, Germany..
    Schraeder, Thomas
    Nordmark Arzneimittel GmbH & Co KG, Uetersen, Germany..
    Kurfuerst, Manfred
    Nordmark Arzneimittel GmbH & Co KG, Uetersen, Germany..
    Andersson, Helene H.
    Univ Hosp, Dept Nephrol & Transplantat, Malmo, Sweden..
    Felldin, Marie
    Univ Hosp, Dept Transplantat, Gothenburg, Sweden..
    Foss, Aksel
    Univ Oslo, Rikshosp, Oslo Univ Hosp, Div Surg,Sect Transplantat, N-0027 Oslo, Norway..
    Salmela, Kaija
    Univ Helsinki, Surg Hosp, Div Transplantat, Helsinki, Finland..
    Tibell, Annika
    Karolinska Inst, Div Transplantat Surg, CLINTEC, Stockholm, Sweden..
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Brandhorst, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    The Effect of Truncated Collagenase Class I Isomers on Human Islet Isolation Outcome2010In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 90, no 3, p. 334-335Article in journal (Refereed)
  • 22.
    Brandhorst, Heide
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Asif, Sana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Andersson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Theisinger, Bastian
    Andersson, Helene H
    Felldin, Maria
    Foss, Aksel
    Salmela, Kaija
    Tibell, Annika
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Brandhorst, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    A new oxygen carrier for improved long-term storage of human pancreata before islet isolation2010In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 89, no 2, p. 155-60Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Pancreas oxygenation during cold storage has been established in islet isolation and transplantation to prevent ischemic tissue damage using perfluorodecalin (PFD) as hyperoxygen carrier. However, studies in humans and pigs provided conflicting results about the efficiency of PFD for pancreas oxygenation. The aim of this study was to compare PFD with a newly developed oxygen carrier composed of perfluorohexyloctane and polydimethylsiloxane 5 (F6H8S5) for long-term storage of human pancreata.

    METHODS: After 24-hr storage in preoxygenated PFD or F6H8S5, pancreata were processed using Liberase HI for pancreas dissociation and a Ficoll gradient for islet purification. Islet quality assessment was performed measuring glucose-stimulated insulin release, viability, islet ATP content, and posttransplant function in diabetic nude mice.

    RESULTS: Compared with PFD, F6H8S5 significantly increased the intrapancreatic partial oxygen pressure and islet ATP content. This corresponded to an increase of islet yield, recovery after culture, glucose stimulation index, viability, and improved graft function in diabetic nude mice.

    CONCLUSIONS: The present findings indicate clearly that F6H8S5 improves isolation outcome after prolonged ischemia compared with PFD. This observation seems to be related to the significant lipophilicity and almost pancreas-specific density of F6H8S5. Moreover, these characteristics facilitate pancreas shipment without using custom-made transport vessels as required for PFD.

  • 23.
    Brandhorst, Heide
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Friberg, Andrew
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Andersson, Helena H.
    Felldin, Maria
    Foss, Aksel
    Salmela, Kaija
    Lundgren, Torbjörn
    Tibell, Annika
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Brandhorst, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    The importance of tryptic-like activity in purified enzyme blends for efficient islet isolation2009In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 87, no 3, p. 370-5Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The isolation of islets from the human pancreas critically depends on an efficient enzyme blend. Previous studies have solely focused on the presence of collagenase and neutral protease/thermolysin. Despite improved characterization of these components, the lot-related variability in efficacy still persists suggesting that additional so far disregarded enzymes are required for efficient islet cleavage. METHODS: Varying activities of a tryptic-like enzyme were identified within collagenase NB1 lots, which were selected according to a matched ratio between tryptic-like and collagenase activity (TLA-ratio). Rat and human pancreata were processed with current standard procedures. RESULTS: Increasing the TLA-ratio from 1.3% to 10% reduced pancreas dissociation time in rats by 50% without affecting islet yield, viability, or posttransplant function in diabetic nude mice. Enhancing the TLA-ratio from 1.3% to 12.6% for human pancreas processing resulted in a significant reduction of recirculation time and increased incrementally human islet yield without affecting purity, in vitro function or recovery after culture. Optimized pancreas digestion correlated with a higher percentage of islet preparations fulfilling quality criteria for clinical transplantation. CONCLUSIONS: We conclude that TLA is an effective component that should be included in moderate amounts in enzyme blends for human islet isolation to optimize the efficiency and minimize the lot-related variability.

  • 24.
    Brandhorst, Heide
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Friberg, Andrew
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Andersson, H. H.
    Felldin, M.
    Foss, A.
    Salmela, K.
    Tibell, A.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Brandhorst, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Large-Scale Comparison of Liberase HI and Collagenase NB1 Utilized for Human Islet Isolation2010In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 19, no 1, p. 3-8Article in journal (Refereed)
    Abstract [en]

    For more than a decade Liberase HI was commonly used as the standard enzyme blend for clinical human islet isolation until enforced replacement by collagenase NB1 (NB1). This change resulted initially in a reduction in islet isolation outcome and transplant activities worldwide. This retrospective study was initiated to compare the efficiency of NB1 premium grade with Liberase in 197 human islet isolations. All pancreata were processed between January 2006 and June 2008 utilizing the same procedures for isolation and quality assessment except the administration of preselected lots of either Liberase (n = 101) or NB1 (n = 96). Utilizing Liberase significantly more digested tissue and purified islet yield was produced compared to NB1. In contrast, the use of NB1 was associated with significantly higher purity and glucose stimulation index during dynamic perifusion. The expression of proinflammatory markers was almost identical except tissue factor expression that was higher after utilization of Liberase. No difference was found in the percentage of pancreata fulfilling the criteria for clinical islet transplantation. The results suggest that Liberase is more efficient for pancreas dissociation than collagenase NB1 but seems to be more harmful to exocrine cells and islet tissue.

  • 25.
    Brandhorst, Heide
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Univ Oxford, Nuffield Dept Surg Sci, Oxford, England;Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.
    Johnson, Paul R.
    Univ Oxford, Nuffield Dept Surg Sci, Oxford, England;Oxford Ctr Diabet Endocrinol & Metab, Oxford, England;Oxford NIHR Biomed Res Ctr, Oxford, England.
    Moench, Johanna
    Nordmark Arzneimittel, Uetersen, Germany.
    Kurfuerst, Manfred
    Nordmark Arzneimittel, Uetersen, Germany.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Brandhorst, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Univ Oxford, Nuffield Dept Surg Sci, Oxford, England;Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.
    Comparison of Clostripain and Neutral Protease as Supplementary Enzymes for Human Islet Isolation2019In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 28, no 2, p. 176-184Article in journal (Refereed)
    Abstract [en]

    Although human islet transplantation has been established as valid and safe treatment for patients with type 1 diabetes, the utilization rates of human pancreases for clinical islet transplantation are still limited and substantially determined by the quality and composition of collagenase blends. While function and integrity of collagenase has been extensively investigated, information is still lacking about the most suitable supplementary neutral proteases. The present study compared islet isolation outcome after pancreas digestion by means of collagenase used alone or supplemented with either neutral protease (NP), clostripain (CP), or both proteases. Decent amounts of islet equivalents (IEQ) were isolated using collagenase alone (3090 +/- 550 IEQ/g), or in combination with NP (2340 +/- 450 IEQ/g) or CP (2740 +/- 280 IEQ/g). Nevertheless, the proportion of undigested tissue was higher after using collagenase alone (21.1 +/- 1.1%, P < 0.05) compared with addition of NP (13.3 +/- 2.2%) or CP plus NP (13.7 +/- 2.6%). Likewise, the percentage of embedded islets was highest using collagenase only (13 +/- 2%) and lowest adding NP plus CP (4 +/- 1%, P < 0.01). The latter combination resulted in lowest post-culture overall survival (42.7 +/- 3.9%), while highest survival was observed after supplementation with CP (74.5 +/- 4.8%, P < 0.01). An insulin response toward glucose challenge was present in all experimental groups, but the stimulation index was significantly decreased using collagenase plus NP (2.0 +/- 0.12) compared with supplementation with CP (3.16 +/- 0.4, P < 0.001). This study demonstrates for the first time that it is possible to isolate significant numbers of human islets combining collagenase only with CP. The supplementation with CP is an effective means to substantially reduce NP activity, which significantly decreases survival and viability after culture. This will facilitate the manufacturing of enzyme blends with less harmful characteristics.

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  • 26.
    Brandhorst, Heide
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.;Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Johnson, Paul R. V.
    Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.;Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford NIHR Biomed Res Ctr, Oxford, England..
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Brandhorst, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.;Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Quantifying the Effects of Different Neutral Proteases on Human Islet Integrity2017In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 26, no 11, p. 1733-1741Article in journal (Refereed)
    Abstract [en]

    Efficient islet release from the pancreas requires the combination of collagenase, neutral protease (cNP), or thermolysin (TL). Recently, it has been shown that clostripain (CP) may also contribute to efficient islet release from the human pancreas. The aim of this study was to evaluate the impact of these proteases on human islet integrity in a prospective approach. Islets were isolated from the pancreas of 10 brain-dead human organ donors. Purified islets were precultured for 3 to 4 d at 37 degrees C to ensure that preparations were cleared of predamaged islets, and only integral islets were subjected to 90 min of incubation at 37 degrees C in Hank's balanced salt solution supplemented with cNP, TL, or CP. The protease concentrations were calculated for a pancreas of 100 g trimmed weight utilizing 120 dimethyl-casein units of cNP, 70,000 caseinase units of TL, or 200 benzoyl-Larginine- ethyl-ester units of CP (1x). These activities were then increased both 5 x and 10 x. After subsequent 24-h culture in enzyme-free culture medium, treated islets were assessed and normalized to sham-treated controls. Compared with controls and CP, islet yield was significantly reduced by using the 5 x activity of cNP and TL, inducing also fragmentation and DNA release. Viability significantly decreased not until adding the 1 x activity of cNP, 5 x activity of TL, or 10 x activity of CP. Although mitochondrial function was significantly lowered by 1 x cNP and 5 x TL, CP did not affect mitochondria at any concentration. cNP-and TL-incubated islets significantly lost intracellular insulin already at 1 x activity, while the 10 x activity of CP had to be added to observe a similar effect. cNP and TL have a similar toxic potency regarding islet integrity. CP also induces adverse effects on islets, but the toxic threshold is generally higher. We hypothesize that CP can serve as supplementary protease to minimize cNP or TL activity for efficient pancreas digestion.

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  • 27.
    Brandhorst, Heide
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.;Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Kurfuerst, Manfred
    Serva Electrophoresis GmbH, Uetersen, Germany..
    Johnson, Paul R.
    Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.;Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford NIHR Biomed Res Ctr, Oxford, England..
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Brandhorst, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.;Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Comparison of Neutral Proteases and Collagenase Class I as Essential Enzymes for Human Islet Isolation2016In: TRANSPLANTATION DIRECT, ISSN 2373-8731, Vol. 2, no 1, article id e47Article in journal (Refereed)
    Abstract [en]

    Background. Efficient islet isolation requires synergistic interaction between collagenase class I (CI) and class II (CII). The CI degradation alters the ratio between CI and CII and is responsible for batch-to-batch variations. This study compares the role of neutral protease (NP) plus clostripain (CP) with CI as essential enzymes for human islet isolation.

    Methods. Human islets were isolated using 4 different enzyme mixtures composed of CII plus either intact (CI-115) or degraded CI (CI-100). Blends were administered either with or without NP/CP. Purified islets were cultured for 3 to 4 days before islet quality assessment.

    Results. Whereas using intact CI-115 without NP/CP did not significantly reduce islet yield (3429 +/- 631 vs 3087 +/- 970 islet equivalent/g, nonsignificant), administration of degraded CI-100 without NP/CP decreased islet yield from 3501 +/- 580 to 1312 +/- 244 islet equivalent/g (P < 0.01), doubled the amount of undigested tissue from 11.8 +/- 1.6 to 24.4 +/- 1.2% (P < 0.01) and triplicated the percentage of trapped islets from 7.7 +/- 2.8 to 22.5 +/- 3.6% (P < 0.05). Islet yield did not vary between supplemented CI-115 and CI-100, but was increased using CI-115 when NP/CP was omitted (P < 0.05). A trend toward higher viability and increased secretory insulin response was noted in both CI-100 and CI-115 when NP/CP was not added.

    Conclusions. This study suggests that NP/CP can compensate reduced CI activity. Future attempts to optimize enzyme blends should consider the possibility to increase the proportion of collagenase CI to reduce the need for potentially harmful NPs.

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  • 28.
    Brandhorst, Heide
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Muehling, B
    Yamaya, H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Henriksnäs, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Brandhorst, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    New class of oxygen carriers improves islet isolation from long-term stored rat pancreata2008In: Transplantation Proceedings, ISSN 0041-1345, E-ISSN 1873-2623, Vol. 40, no 2, p. 393-394Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Pancreas shipment is frequently associated with prolonged ischemia deteriorating islet graft function. The strategy to prevent ischemic damage utilizing perfluorodecalin (PFD) for human pancreas oxygenation does not seem to improve isolation outcome. The present study investigated the efficiency of perfluorohexyloctane (F6H8), a hyperoxygen carrier characterized by low specific density (1.33 g/cm3) and lipophilic qualities, to facilitate islet isolation from long-term stored rat pancreata. MATERIALS AND METHODS: Prior to islet isolation, pancreata were intraductally flushed in situ with Kyoto solution (KS) and stored for 24 hours in KS, oxygenated PFD, or F6H8. RESULTS: Islet isolation performed after 24-hour storage in KS failed completely. The intrapancreatic pO2 in PFD- and F6H8-incubated pancreata was almost the same. In correspondence, the ATP content and viability of isolated islets were similar as well. In contrast, islet yield and in vitro function were significantly reduced after storage in PFD compared with F6H8. CONCLUSION: This study suggested that islet isolation performed after long-term pancreas preservation can be significantly improved utilizing semifluorinated alkanes as oxygen carriers.

  • 29.
    Brandhorst, Heide
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Raemsch-Guenther, N.
    Raemsch, C.
    Friedrich, O.
    Kurfuerst, M.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Brandhorst, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Degraded collagenase deteriorates islet viability2008In: Transplantation Proceedings, ISSN 0041-1345, E-ISSN 1873-2623, Vol. 40, no 2, p. 370-371Article in journal (Refereed)
    Abstract [en]

    Objective. The utilization of purified enzyme blends consisting of collagenase class I (CI) and II (CII) and neutral protease is an essential step for clinical islet isolation. Previous studies suggested that the use of enzyme lots containing degraded CI reduced islet release from human pancreata. The present study sought to assess the effect of degraded collagenase on islet function in vitro and posttransplantation. Materials and Methods. Crude collagenase was chromatographically separated into CI, CII, and a mixture of degraded CI and CII isomers. Subsequently, classes were recombined to obtain a CII/CI ratio of 0.5. Rat islets were isolated utilizing neutral protease and 20 units of recombined collagenase containing either intact (Ci) or degraded isomers (Cd). Results. Digestion time was reduced utilizing Cd (P < .001). The highest islet yield and lowest islet fragmentation were obtained with Ci (P < .01). Utilization of Cd corresponded to a reduction in viability and in vitro function (NS). Islet transplantation reversed hyperglycemia in diabetic nude mice, but revealed an absence of weight gain in recipients receiving islets isolated using Cd (P < .01). Conclusion. This study suggested that islet function posttransplantation is affected by degraded collagenase isomers. This finding has to be considered for the purification process of collagenase.

  • 30.
    Brandhorst, Heide
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Raemsch-Guenther, Nicole
    Raemsch, Christian
    Friedrich, Olaf
    Huettler, Silke
    Kurfuerst, Manfred
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Brandhorst, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    The ratio between collagenase class I and class II influences the efficient islet release from the rat pancreas2008In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 85, no 3, p. 456-61Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Previous studies indicated different roles of collagenase class I, class II and neutral protease in the enzymatic islet release from pancreatic tissue. Because no information has been available, this study was aimed to investigate the isolation efficiency of different ratios between collagenase class II and I (C-ratio) in the rat pancreas serving as model for the human pancreas without being restricted by the large variability observed in human donors. METHODS: Rat pancreata were digested using a marginal neutral protease activity and 20 PZ-U of purified collagenase classes recombined to create a C-ratio of 0.5, 1.0, or 1.5. Collagenase efficiency was evaluated in terms of isolation outcome and posttransplantation function in diabetic nude mice. RESULTS: The highest yield of freshly isolated islets was obtained using a C-ratio of 1.0. Purity and fragmentation of freshly isolated islets were not influenced by the C-ratio. After 24-hr culture performed for quality assessment, a marginal but significant reduction of viability was observed in islets isolated by means of a C-ratio of 0.5 and 1.5. Islet in vitro and posttransplantation function revealed no negative effect mediated by different C-ratios. CONCLUSIONS: The present study demonstrates that the C-ratio is of significant relevance for the outcome after enzymatic rat islet isolation. The data indicate further that purified collagenase class I or class II does not damage islet tissue even if used in excess. The present study can serve as a start for subsequent experiments in the human pancreas.

  • 31.
    Brandhorst, Heide
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Theisinger, Bastian
    Yamaya, Hideyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Henriksnäs, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Brandhorst, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Perfluorohexyloctane improves long-term storage of rat pancreata for subsequent islet isolation2009In: Transplant International, ISSN 0934-0874, E-ISSN 1432-2277, Vol. 22, no 10, p. 1017-1022Article in journal (Refereed)
    Abstract [en]

    Pancreas oxygenation by means of the hyperoxygen carrier perfluorodecalin (PFD) has been established to prevent ischemically induced damage from cold-stored pancreata. However, large-scale studies did not confirm the promising results that had been observed in smaller donor populations. This study assessed whether islet isolation from pancreata stored for prolonged periods can be improved by utilizing the new oxygen carrier perfluorohexyloctane (F6H8) characterized by lower gravity and higher lipophilicity than PFD. Subsequent to 24 h of storage in either oxygenated PFD or F6H8, the rat pancreata were assessed for the intrapancreatic partial oxygen pressure (pO(2)) and subsequently processed with current standard procedures. The intrapancreatic pO(2) was nearly identical in rat pancreata stored either in PFD or F6H8. Nevertheless, rat islet isolation outcome was significantly increased in terms of yield, integrity, in vitro function and post-transplant outcome after transplantation in diabetic nude mice when F6H8 was used as oxygen carrier. This proof-of-concept study demonstrated in rats that islet isolation performed after long-term storage of oxygenated pancreatic tissue can be significantly improved if PFD was replaced by F6H8.

  • 32.
    Caballero-Corbalan, José
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Brandhorst, Heide
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Asif, Sana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Engelse, Marten
    Leiden Univ, Med Ctr, Dept Nephrol, Leiden, Netherlands.
    de Koning, Eelco
    Leiden Univ, Med Ctr, Dept Nephrol, Leiden, Netherlands.
    Pattou, Francois
    Univ Hosp, INSERM ERIT M 0106 Diabet Cell Therapy, Lille, France.
    Kerr-Conte, Julie
    Univ Hosp, INSERM ERIT M 0106 Diabet Cell Therapy, Lille, France.
    Brandhorst, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Mammalian Tissue-Free Liberase: A New GMP-Graded Enzyme Blend for Human Islet Isolation2010In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 90, no 3, p. 332-333Article in journal (Refereed)
  • 33.
    Caballero-Corbalán, José
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Brandhorst, Heide
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Malm, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Felldin, Marie
    Foss, Aksel
    Salmela, Kaija
    Tibell, Annika
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Brandhorst, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Using HTK for Prolonged Pancreas Preservation Prior to Human Islet Isolation2012In: Journal of Surgical Research, ISSN 0022-4804, E-ISSN 1095-8673, Vol. 175, no 1, p. 163-168Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Histidine-tryptophan-ketoglutarate (HTK) has been established as an alternative to University-of-Wisconsin solution (UWS) for abdominal organ preservation, but data about HTK efficiency to preserve pancreata during prolonged cold ischemia time (CIT) are conflicting. In human islet transplantation, HTK provided similar isolation outcomes after short CIT. The present study aimed to investigate whether islets can be successfully isolated from HTK-preserved pancreata after prolonged CIT compared with UWS.

    MATERIALS AND METHODS: Sixty-four human pancreata retrieved from donors meeting criteria for kidney donation were perfused utilizing either HTK or UWS and preserved for more or less than 10 h prior to islet isolation. Along with parameters related to isolation and islet quality assessment, the dry-to-wet weight ratio was evaluated.

    RESULTS: Donor- and procurement-related factors did not vary between HTK- and UWS-perfused pancreata. The dry-to-wet weight ratio was lower in HTK-preserved pancreata indicated tissue edema (21.0% ± 3.5% versus 24.8% ± 2.0%, P = 0.007). Isolation-related variables differed between experimental groups after prolonged CIT with respect to purified packed tissue volume (9.1 ± 5.0 versus 17.2 ± 8.1 μL/g, P = 0.004) and islet yield (1910 ± 980 versus 3150 ± 1420 IE/g, P = 0.012). Islet purity and survival after culture were similar after HTK or UWS perfusion. The preservation solution did not affect in vitro function and transplantability of isolated islets.

    CONCLUSIONS: Compared with UWS, HTK has similar efficiency to preserve human pancreata for subsequent islet isolation during <10 h CIT but seems to be limited for prolonged cold storage.

  • 34.
    Caballero-Corbalán, José
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Eich, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Lundgren, Torbjörn
    Foss, Aksel
    Felldin, Marie
    Källen, Ragnar
    Salmela, Kalja
    Tibell, Annika
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Brandhorst, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    No beneficial effect of two-layer storage compared with UW-storage on human islet isolation and transplantation2007In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 84, no 7, p. 864-869Article in journal (Refereed)
    Abstract [en]

    Background. Shipment of pancreata between distant centers is frequently associated with prolonged cold ischemia time (CIT) that leads to poorer outcomes for islet transplantation. Clinical pilot trials have indicated that oxygenation of explanted human pancreata utilizing the two-layer method (TLM) allows the use of marginal donor pancreata for islet transplantation. The present study aimed to clarify whether TLM enhances the ischemic tolerance of human pancreata. Methods. We analyzed retrospectively the outcome of 200 human islet isolations performed after TLM preservation or storage in University of Wisconsin solution (UWS). Results. Donor characteristics and digestion parameters did not vary significantly between TLM-preserved and UWS-stored pancreata. No differences were observed between experimental groups with regard to islet yield, purity, or dynamic glucose stimulation index after either short or prolonged CIT. However, CIT and stimulation index were negatively correlated in each experimental group. The isolation outcome in donors aged ≥60 years was not increased after TLM preservation when compared to UWS storage. No effect was observed regarding islet posttransplant function in recipients with established kidney grafts. Conclusions. The present study suggests that the ischemic tolerance of human pancreata cannot be extended by TLM preservation. In addition, TLM does not seem to improve the isolation outcome for pancreata from elderly donors.

  • 35.
    Caballero-Corbalán, José
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Friberg, Andrew S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Brandhorst, Heide
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Andersson, Helene H.
    Felldin, Maria
    Foss, Aksel
    Salmela, Kaija
    Tibell, Annika
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Brandhorst, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Vitacyte Collagenase HA: A Novel Enzyme Blend for Efficient Human Islet Isolation2009In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 88, no 12, p. 1400-1402Article in journal (Refereed)
  • 36.
    Cabric, Sanja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Eich, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Sanchez, Javier
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    A new method for incorporating functional heparin onto the surface of islets of Langerhans2008In: Tissue Engineering. Part C, Methods, ISSN 1937-3384, Vol. 14, no 2, p. 141-147Article in journal (Refereed)
    Abstract [en]

    A novel technique is described to conjugate macromolecular heparin complexes to cell surfaces. The method is based on the dual properties of avidin-expressing binding sites for both biotin and a macromolecular complex of heparin. A quartz crystal microbalance with dissipation monitoring (QCM-D) revealed sequential binding of biotin, avidin, and heparin complexes. Large particle flow cytometry confirmed functional integrity. Confocal microscopy of the heparinized islets showed evenly distributed fluorescence. An in vitro Chandler loop model demonstrated that the biocompatibility of the new method is comparable to the previous method used on artificial materials with regard to coagulation and antithrombin uptake. The technique presented allows human islets of Langerhans to successfully be covered with functional heparin as a means to reduce instant blood-mediated inflammatory reactions induced by the innate immune system.

  • 37.
    Cabric, Sanja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Sanchez, Javier
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Johansson, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Magnusson, Peetra U.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Anchoring of vascular endothelial growth factor to surface-immobilized heparin on pancreatic islets: implications for stimulating islet angiogenesis2010In: Tissue engineering. Part A, ISSN 1937-3341, Vol. 16, no 3, p. 961-970Article in journal (Refereed)
    Abstract [en]

    In pancreatic islet transplantation, early revascularization is necessary for long-term graft function. We have shown in in vitro and in vivo models that modification with surface-attached heparin protects the islets from acute attack by the innate immune system of the blood following intraportal islet transplantation. In this study, we have investigated the ability of an immobilized conjugate composed of heparin to bind the angiogenic growth factor vascular endothelial growth factor-A (VEGF-A) as a means of attracting endothelial cells (ECs) to induce angiogenesis and revascularization. We analyzed the capacity of VEGF-A to bind to immobilized heparin and how this affected the proliferation and adherence of ECs to both artificial glass surfaces and islets. Quartz crystal microbalance with dissipation monitoring and slot-blot demonstrated the binding of VEGF-A to heparin-coated surfaces upon which ECs showed protein-dependent proliferation. Also, ECs cultured on heparin-coated glass surfaces exhibited effects upon focal contacts. Heparinized islets combined with VEGF-A demonstrated unaffected insulin release. Further, covering islets with heparin also increased the adhesion of ECs to the islet surface. Immobilized heparin on the islet surface may be a useful anchor molecule for achieving complete coverage of islets with angiogenic growth factors, ultimately improving islet revascularization and engraftment in pancreatic islet transplantation.

  • 38.
    Cabric, Sanja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Sanchez, Javier
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Lundgren, Torbjörn
    Foss, Aksel
    Felldin, Marie
    Källen, Ragnar
    Salmela, Kaija
    Tibell, Annika
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Islet Surface Heparinization Prevents the Instant-Blood Mediated Inflammatory Reaction in Islet Transplantation2007In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 56, no 8, p. 2008-2015Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE—In clinical islet transplantation, the instant blood-mediated inflammatory reaction (IBMIR) is a major factor contributing to the poor initial engraftment of the islets. This reaction is triggered by tissue factor and monocyte chemoattractant protein (MCP)-1, expressed by the transplanted pancreatic islets when the islets come in contact with blood in the portal vein. All currently identified systemic inhibitors of the IBMIR are associated with a significantly increased risk of bleeding or other side effects. To avoid systemic treatment, the aim of the present study was to render the islet graft blood biocompatible by applying a continuous heparin coating to the islet surface.

    RESEARCH DESIGN AND METHODS—A biotin/avidin technique was used to conjugate preformed heparin complexes to the surface of pancreatic islets. This endothelial-like coating was achieved by conjugating barely 40 IU heparin per full-size clinical islet transplant.

    RESULTS—Both in an in vitro loop model and in an allogeneic porcine model of clinical islet transplantation, this heparin coating provided protection against the IBMIR. Culturing heparinized islets for 24 h did not affect insulin release after glucose challenge, and heparin-coated islets cured diabetic mice in a manner similar to untreated islets.

    CONCLUSIONS—This novel pretreatment procedure prevents intraportal thrombosis and efficiently inhibits the IBMIR without increasing the bleeding risk and, unlike other pretreatment procedures (e.g., gene therapy), without inducing acute or chronic toxicity in the islets.

  • 39. Campbell-Thompson, M. L.
    et al.
    Atkinson, M. A.
    Butler, A. E.
    Chapman, N. M.
    Frisk, Gun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Gianani, R.
    Giepmans, B. N.
    von Herrath, M. G.
    Hyoty, H.
    Kay, T. W.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Morgan, N. G.
    Powers, A. C.
    Pugliese, A.
    Richardson, S. J.
    Rowe, P. A.
    Tracy, S.
    Veld, P. A. In't
    The diagnosis of insulitis in human type 1 diabetes2013In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, no 11, p. 2541-2543Article in journal (Refereed)
  • 40.
    Carlbom, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Espes, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Pancreatic perfusion and subsequent response to glucose in healthy individuals and patients with type 1 diabetes2016In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, no 9, p. 1968-1972Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: The aim of this study was to investigate pancreatic perfusion and its response to a glucose load in patients with type 1 diabetes mellitus compared with non-diabetic ('healthy') individuals.

    METHODS: Eight individuals with longstanding type 1 diabetes and ten sex-, age- and BMI-matched healthy controls underwent dynamic positron emission tomography scanning with (15)O-labelled water before and after intravenous administration of glucose. Perfusion in the pancreas was measured. Portal and arterial hepatic perfusion were recorded as references.

    RESULTS: Under fasting conditions, total pancreatic perfusion was on average 23% lower in the individuals with diabetes compared with healthy individuals. Glucose increased total pancreatic and portal hepatic blood perfusion in healthy individuals by 48% and 38%, respectively. In individuals with diabetes there was no significant increase in either total pancreatic or portal hepatic perfusion.

    CONCLUSIONS/INTERPRETATION: Individuals with type 1 diabetes have reduced basal pancreatic perfusion and a severely impaired pancreatic and splanchnic perfusion response to intravenous glucose stimulation.

  • 41.
    Carlbom, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Espes, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Martinell, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    [(11)C]5-Hydroxy-Tryptophan PET for Assessment of Islet Mass During Progression of Type 2 Diabetes2017In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, no 5, p. 1286-1292Article in journal (Refereed)
    Abstract [en]

    [(11)C]5-hydroxy-tryptophan ([(11)C]5-HTP) PET of the pancreas has been shown to be a surrogate imaging biomarker of pancreatic islet mass. The change in islet mass in different stages of type 2 diabetes (T2D) as measured by non-invasive imaging is currently unknown. Here, we describe a cross-sectional study where subjects at different stages of T2D development with expected stratification of pancreatic islet mass were examined in relation to non-diabetic individuals. The primary outcome was the [(11)C]5-HTP uptake and retention in pancreas, as a surrogate marker for the endogenous islet mass.We found that metabolic testing indicated a progressive loss of beta cell function, but that this was not mirrored by a decrease in [(11)C]5-HTP tracer accumulation in the pancreas. This provides evidence of retained islet mass despite decreased beta cell function. The results herein indicates that beta cell dedifferentiation, and not necessarily endocrine cell loss, constitute a major cause of beta cell failure in T2D.

  • 42.
    Carlbom, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Weis, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Pre-transplantation ³¹P-magnetic resonance spectroscopy for quality assessment of human pancreatic grafts: A feasibility study2017In: Magnetic Resonance Imaging, ISSN 0730-725X, E-ISSN 1873-5894, Vol. 39, p. 98-102Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate the feasibility of using (31)P-MRS for objective non-invasive quality assessment of human pancreas grafts prior to transplantation or islet isolation.

    Materials and methods: Pancreata from 5 human donors, 3 males and 2 females, aged 49-78years, with body mass index (BMI) 22-31kg/m(2), were included. Pancreata were perfused with histidine-tryptophan-ketoglutarate solution during procurement and stored in hypothermic condition (4°C) for 21-44h. During the period of hypothermic storage repeated spectra were obtained for each graft by (31)P-MRS (1.5Tesla) to measure the cold ischemia time (CIT) dependent changes of the phosphorous metabolites adenosine triphosphate (ATP), phosphomonoesters (PME), phosphodiesters (PDE) and inorganic phosphate (Pi), in the grafts. Graft temperature was measured immediately before and after MR-examination. Reference spectrum for non-viable tissue was obtained after graft exposure to room temperature.

    Results: PME/Pi, PDE/Pi and ATP/Pi spectral intensities ratios decreased with increasing CIT, reflecting the decreased viability of the grafts. PME/Pi ratio was the most discriminatory variable at prolonged CIT. (31)P-MRS could be performed without significantly increasing graft temperature.

    Conclusions: (31)P-MRS may provide quantitative parameters for evaluating graft viability ex vivo, and is a promising tool for objective non-invasive assessment of the quality of human pancreas grafts prior to transplantation or islet isolation.

  • 43.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Espes, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sedigh, Amir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Rotem, Avi
    Zimermann, Baruch
    Grinberg, Helena
    Goldman, Tali
    Barkai, Uriel
    Avni, Yuval
    Westermark, Gunilla T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlbom, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Antaros Medical AB, Mölndal, Sweden.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Olerud, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Transplantation of macroencapsulated human islets within the bioartificial pancreas βAir to patients with type 1 diabetes mellitus2018In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 18, no 7, p. 1735-1744Article in journal (Refereed)
    Abstract [en]

    Macroencapsulation devices provide the dual possibility to immunoprotect transplanted cells while also being retrievable; the latter bearing importance for safety in future trials with stem-cell derived cells. However, macroencapsulation entails a problem with oxygen supply to the encapsulated cells. The βAir device solves this with an incorporated refillable oxygen tank. This phase 1 study evaluated the safety and efficacy of implanting the βAir device containing allogeneic human pancreatic islets to patients with type 1 diabetes. Four patients were transplanted with 1-2 βAir devices, each containing 155000-180000 IEQ (i.e. 1800-4600 IEQ per kg body weight), and monitored for 3-6 months, followed by the recovery of devices. Implantation of the βAir device was safe and successfully prevented immunization and rejection of the transplanted tissue. However, although beta cells survived in the device, only minute levels of circulating C-peptide were observed with no impact on metabolic control. Fibrotic tissue with immune cells was formed in capsule surroundings. Recovered devices displayed a blunted glucose-stimulated insulin response, and amyloid formation in the endocrine tissue. We conclude that the βAir device is safe and can support survival of allogeneic islets for several months, although the function of the transplanted cells was limited.

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  • 44.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Le Blanc, Katarina
    Mesenchymal Stromal Cells to Halt the Progression of Type 1 Diabetes?2015In: Current Diabetes Reports, ISSN 1534-4827, E-ISSN 1539-0829, Vol. 15, no 7, article id 46Article in journal (Refereed)
    Abstract [en]

    No treatment to halt the progressive loss of insulin-producing beta-cells in type 1 diabetes mellitus has yet been clinically introduced. Strategies tested have at best only transiently preserved beta-cell function and in many cases with obvious side effects of drugs used. Several studies have suggested that mesenchymal stromal cells exert strong immunomodulatory properties with the capability to prevent or halt diabetes development in animal models of type 1 diabetes. A multitude of mechanisms has been forwarded to exert this effect. Recently, we translated this strategy into a first clinical phase I/IIa trial and observed no side effects, and preserved or even increased C-peptide responses to a mixed meal tolerance test during the first year after treatment. Future blinded, larger studies, with extended follow-up, are clearly of interest to investigate this treatment concept.

  • 45.
    Carlsson, Per-Ola
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Schwarcz, Erik
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Le Blanc, Katarina
    Preserved Beta-Cell Function in Type 1 Diabetes by Mesenchymal Stromal Cells2015In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, no 2, p. 587-592Article in journal (Refereed)
    Abstract [en]

    The retention of endogenous insulin secretion in type 1 diabetes is an attractive clinical goal, which opens possibilities for long-term restoration of glucose metabolism. Mesenchymal stromal cells (MSCs) constitute, based on animal studies, a promising interventional strategy for the disease. This prospective clinical study describes the translation of this cellular intervention strategy to patients with recent onset type 1 diabetes. Twenty adult patients with newly diagnosed type 1 diabetes were enrolled and randomized to MSC treatment or to the control group. Residual beta-cell function was analyzed as C-peptide concentrations in blood in response to a mixed meal tolerance test (MMTT) at one-year follow-up. In contrast to the patients in the control arm, who showed loss in both C-peptide peak values and C-peptide when calculated as area under the curve during the first year, these responses were preserved or even increased in the MSC-treated patients. Importantly, no side effects of MSC treatment were observed. We conclude that autologous MSC treatment in new onset type 1 diabetes constitute a safe and promising strategy to intervene in disease progression and preserve beta-cell function.

  • 46.
    Cheung, Pierre
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Translational PET Imaging.
    Amin, Mohammad A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Zhang, Bo
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Translational PET Imaging.
    Lechi, Francesco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Translational PET Imaging. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Eriksson, Olof
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Translational PET Imaging.
    [18F]MK-7246 for Positron Emission Tomography Imaging of the Beta-Cell Surface Marker GPR442023In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 15, no 2, article id 499Article in journal (Refereed)
    Abstract [en]

    The progressive loss of beta-cell mass is a hallmark of diabetes and has been suggested as a complementary approach to studying the progression of diabetes in contrast to the beta-cell function. Non-invasive nuclear medicinal imaging techniques such as Positron Emission Tomography using radiation emitting tracers have thus been suggested as more viable methodologies to visualize and quantify the beta-cell mass with sufficient sensitivity. The transmembrane G protein-coupled receptor GPR44 has been identified as a biomarker for monitoring beta-cell mass. MK-7246 is a GPR44 antagonist that selectively binds to GPR44 with high affinity and good pharmacokinetic properties. Here, we present the synthesis of MK-7246, radiolabeled with the positron emitter fluorine-18 for preclinical evaluation using cell lines, mice, rats and human pancreatic cells. Here, we have described a synthesis and radiolabeling method for producing [18F]MK-7246 and its precursor compound. Preclinical assessments demonstrated the strong affinity and selectivity of [18F]MK-7246 towards GPR44. Additionally, [18F]MK-7246 exhibited excellent metabolic stability, a fast clearance profile from blood and tissues, qualifying it as a promising radioactive probe for GPR44-directed PET imaging.

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  • 47.
    Cheung, Pierre
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Translational PET Imaging.
    Persson, Jonas
    Zhang, Bo
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Translational PET Imaging.
    Khalil, Amina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Translational PET Imaging. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Huang, Zhijun
    Lindskog, Cecilia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
    Ståhl, Stefan
    Löfblom, John
    Eriksson, Olof
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Translational PET Imaging.
    Lead compound identification from first-in-class high affinity Affibody molecules binders towards DGCR2Manuscript (preprint) (Other academic)
  • 48.
    Cheung, Pierre
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Translational PET Imaging.
    Thorngren, Julia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Zhang, Bo
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Translational PET Imaging.
    Vasylovska, Svitlana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lechi, Francesco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Translational PET Imaging. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Persson, Jonas
    Ståhl, Stefan
    Löfblom, John
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer Immunotherapy.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lau, Joey
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Eriksson, Olof
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Translational PET Imaging.
    Preclinical evaluation of Affibody molecule 18F-TZ-ZAM106 for PET imaging of DGCR2Manuscript (preprint) (Other academic)
  • 49.
    Cheung, Pierre
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Translational PET Imaging.
    Thorngren, Julia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Zhang, Bo
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Translational PET Imaging.
    Vasylovska, Svitlana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lechi, Francesco
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Translational PET Imaging.
    Persson, Jonas
    Department of Protein Science, Division of Protein Engineering, KTH Royal Institute of Technology, Stockholm, Sweden.
    Ståhl, Stefan
    Department of Protein Science, Division of Protein Engineering, KTH Royal Institute of Technology, Stockholm, Sweden.
    Löfblom, John
    Department of Protein Science, Division of Protein Engineering, KTH Royal Institute of Technology, Stockholm, Sweden.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Eriksson, Jonas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Lau, Joey
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Eriksson, Olof
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Preclinical evaluation of Affibody molecule for PET imaging of human pancreatic islets derived from stem cells.2023In: EJNMMI Research, E-ISSN 2191-219X, EJNMMI research, ISSN 2191-219X, Vol. 13, no 1, p. 107-, article id 107Article in journal (Refereed)
    Abstract [en]

    BackgroundBeta-cell replacement methods such as transplantation of isolated donor islets have been proposed as a curative treatment of type 1 diabetes, but widespread application is challenging due to shortages of donor tissue and the need for continuous immunosuppressive treatments. Stem-cell-derived islets have been suggested as an alternative source of beta cells, but face transplantation protocols optimization difficulties, mainly due to a lack of available methods and markers to directly monitor grafts survival, as well as their localization and function. Molecular imaging techniques and particularly positron emission tomography has been suggested as a tool for monitoring the fate of islets after clinical transplantation. The integral membrane protein DGCR2 has been demonstrated to be a potential pancreatic islet biomarker, with specific expression on insulin-positive human embryonic stem-cell-derived pancreatic progenitor cells. The candidate Affibody molecule ZDGCR2:AM106 was radiolabeled with fluorine-18 using a novel click chemistry-based approach. The resulting positron emission tomography tracer [18F]ZDGCR2:AM106 was evaluated for binding to recombinant human DGCR2 and cryosections of stem-cell-derived islets, as well as in vivo using an immune-deficient mouse model transplanted with stem-cell-derived islets. Biodistribution of the [18F]ZDGCR2:AM106 was also assessed in healthy rats and pigs.

    Results[18F]ZDGCR2:AM106 was successfully synthesized with high radiochemical purity and yield via a pretargeting approach. [18F]ZDGCR2:AM106 retained binding to recombinant human DCGR2 as well as to cryosectioned stem-cell-derived islets, but in vivo binding to native pancreatic tissue in both rat and pig was low. However, in vivo uptake of [18F]ZDGCR2:AM106 in stem-cell-derived islets transplanted in the immunodeficient mice was observed, albeit only within the early imaging frames after injection of the radiotracer.

    ConclusionTargeting of DGCR2 is a promising approach for in vivo detection of stem-cell-derived islets grafts by molecular imaging. The synthesis of [18F]ZDGCR2:AM106 was successfully performed via a pretargeting method to label a site-specific covalently bonded fluorine-18 to the Affibody molecule. However, the rapid washout of [18F]ZDGCR2:AM106 from the stem-cell-derived islets graft indicates that dissociation kinetics can be improved. Further studies using alternative binders of similar classes with improved binding potential are warranted.

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  • 50.
    Cheung, Pierre
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Translational PET Imaging.
    Zhang, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Translational PET Imaging. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Puuvuori, Emmi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Translational PET Imaging. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Amin, Mohammad A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Ye, Sofie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Eriksson, Olof
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Translational PET Imaging.
    PET Imaging of GPR44 by Antagonist [C-11]MK-7246 in Pigs2021In: Biomedicines, E-ISSN 2227-9059, Vol. 9, no 4, article id 434Article in journal (Refereed)
    Abstract [en]

    A validated imaging marker for beta-cell mass would improve understanding of diabetes etiology and enable new strategies in therapy development. We previously identified the membrane-spanning protein GPR44 as highly expressed and specific to the beta cells of the pancreas. The selective GPR44 antagonist MK-7246 was radiolabeled with carbon-11 and the resulting positron-emission tomography (PET) tracer [C-11]MK-7246 was evaluated in a pig model and in vitro cell lines. The [C-11]MK-7246 compound demonstrated mainly hepatobiliary excretion with a clearly defined pancreas, no spillover from adjacent tissues, and pancreatic binding similar in magnitude to the previously evaluated GPR44 radioligand [C-11]AZ12204657. The binding could be blocked by preadministration of nonradioactive MK-7246, indicating a receptor-binding mechanism. [C-11]MK-7246 showed strong potential as a PET ligand candidate for visualization of beta-cell mass (BCM) and clinical translation of this methodology is ongoing.

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