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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, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, 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.

  • 2.
    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, 1402-1411 p.Article 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.

  • 3.
    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
    Brandhorst, Heide
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Jorns, Carl
    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
    Theisinger, Sonja
    Hoeger, Simone
    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, 959-967 p.Article 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.

  • 4. 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, 78-86 p.Article 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.

  • 5.
    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, S1-S44 p.Article in journal (Refereed)
  • 6. 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, 312- p.Article in journal (Refereed)
  • 7. 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, 176- p.Article in journal (Refereed)
  • 8.
    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, 65-71 p.Article 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.

  • 9.
    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, 310-322 p.Article 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.

  • 10.
    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, 105-108 p.Article 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. 

  • 11.
    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, 27-33 p.Article 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.

  • 12.
    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, e5-7 p.Article in journal (Refereed)
  • 13.
    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, 1477-1483 p.Article 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.

  • 14.
    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, 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.

  • 15.
    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, 456-61 p.Article 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.

  • 16.
    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, 163-168 p.Article 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.

  • 17.
    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, 864-869 p.Article 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.

  • 18.
    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, 961-970 p.Article 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.

  • 19. 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, 2541-2543 p.Article in journal (Refereed)
  • 20.
    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, 1968-1972 p.Article 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.

  • 21.
    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, 1286-1292 p.Article 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.

  • 22.
    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, 98-102 p.Article 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.

  • 23.
    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, 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.

  • 24.
    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, 587-592 p.Article 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.

  • 25.
    Cooper, David K. C.
    et al.
    Thomas E Starzl Transplantat Inst, Pittsburgh, PA USA..
    Bottino, Rita
    Allegheny Singer Res Inst, Inst Cellular Therapeut, 320 E N Ave, Pittsburgh, PA 15212 USA..
    Gianello, Pierre
    Catholic Univ Louvain, Fac Med, Expt Surg Lab, Brussels, Belgium..
    Graham, Melanie
    Univ Minnesota, Preclin Res Ctr, Dept Surg, St Paul, MN 55108 USA..
    Hawthorne, Wayne J.
    Univ Sydney, Westmead Hosp, Dept Surg, Westmead, NSW 2145, Australia..
    Kirk, Allan D.
    Duke Univ, Sch Med, Dept Surg, Durham, NC USA..
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Park, Chung-Gyu
    Seoul Natl Univ, Dept Microbiol & Immunol, Dept Biomed Sci, Xenotransplantat Res Ctr,Coll Med, Seoul, South Korea..
    Weber, Collin
    Emory Univ, Sch Med, Dept Surg, Atlanta, GA 30322 USA..
    First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes - Chapter 4: pre-clinical efficacy and complication data required to justify a clinical trial2016In: Xenotransplantation, ISSN 0908-665X, E-ISSN 1399-3089, Vol. 23, no 1, 46-52 p.Article in journal (Refereed)
    Abstract [en]

    In 2009, the International Xenotransplantation Association (IXA) published a consensus document that provided guidelines and recommendations (not regulations) for those contemplating clinical trials of porcine islet transplantation. These guidelines included the IXA's opinion on what constituted rigorous pre-clinical studies using the most relevant animal models and were based on non-human primate testing. We now report our discussion following a careful review of the 2009 guidelines as they relate to pre-clinical testing. In summary, we do not believe there is a need to greatly modify the conclusions and recommendations of the original consensus document. Pre-clinical studies should be sufficiently rigorous to provide optimism that a clinical trial is likely to be safe and has a realistic chance of success, but need not be so demanding that success might only be achieved by very prolonged experimentation, as this would not be in the interests of patients whose quality of life might benefit immensely from a successful islet xenotransplant. We believe these guidelines will be of benefit to both investigators planning a clinical trial and to institutions and regulatory authorities considering a proposal for a clinical trial. In addition, we suggest consideration should be given to establishing an IXA Clinical Trial Advisory Committee that would be available to advise (but not regulate) researchers considering initiating a clinical trial of xenotransplantation.

  • 26.
    Danielsson, Angelika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fagerberg, Linn
    Hallstrom, Bjorn M.
    Schwenk, Jochen M.
    Uhlen, Mathias
    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.
    Lindskog, Cecilia Bergström
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The Human Pancreas Proteome Defined by Transcriptomics and Antibody-Based Profiling2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 12, e115421- p.Article in journal (Refereed)
    Abstract [en]

    The pancreas is composed of both exocrine glands and intermingled endocrine cells to execute its diverse functions, including enzyme production for digestion of nutrients and hormone secretion for regulation of blood glucose levels. To define the molecular constituents with elevated expression in the human pancreas, we employed a genome-wide RNA sequencing analysis of the human transcriptome to identify genes with elevated expression in the human pancreas. This quantitative transcriptomics data was combined with immunohistochemistry-based protein profiling to allow mapping of the corresponding proteins to different compartments and specific cell types within the pancreas down to the single cell level. Analysis of whole pancreas identified 146 genes with elevated expression levels, of which 47 revealed a particular higher expression as compared to the other analyzed tissue types, thus termed pancreas enriched. Extended analysis of in vitro isolated endocrine islets identified an additional set of 42 genes with elevated expression in these specialized cells. Although only 0.7% of all genes showed an elevated expression level in the pancreas, this fraction of transcripts, in most cases encoding secreted proteins, constituted 68% of the total mRNA in pancreas. This demonstrates the extreme specialization of the pancreas for production of secreted proteins. Among the elevated expression profiles, several previously not described proteins were identified, both in endocrine cells (CFC1, FAM159B, RBPJL and RGS9) and exocrine glandular cells (AQP12A, DPEP1, GATM and ERP27). In summary, we provide a global analysis of the pancreas transcriptome and proteome with a comprehensive list of genes and proteins with elevated expression in pancreas. This list represents an important starting point for further studies of the molecular repertoire of pancreatic cells and their relation to disease states or treatment effects.

  • 27.
    Davies, Lindsay C.
    et al.
    Karolinska Inst, Ctr Hematol & Regenerat Med, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Clin Immunol, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Transfus Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Alm, Jessica J.
    Karolinska Inst, Ctr Hematol & Regenerat Med, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Clin Immunol, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Transfus Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Heldring, Nina
    Karolinska Inst, Ctr Hematol & Regenerat Med, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Clin Immunol, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Transfus Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Moll, Guido
    Karolinska Inst, Ctr Hematol & Regenerat Med, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Clin Immunol, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Transfus Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Gavin, Caroline
    Karolinska Inst, Ctr Hematol & Regenerat Med, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Clin Immunol, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Transfus Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Batsis, Ioannis
    Karolinska Inst, Ctr Hematol & Regenerat Med, Stockholm, Sweden..
    Qian, Hong
    Karolinska Inst, Ctr Hematol & Regenerat Med, Stockholm, Sweden..
    Sigvardsson, Mikael
    Linkoping Univ, Inst Clin & Expt Med, Linkoping, Sweden..
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Kyllonen, Lauri E.
    Helsinki Univ Hosp, Div Transplantat, Helsinki, Finland..
    Salmela, Kaija T.
    Helsinki Univ Hosp, Div Transplantat, Helsinki, Finland..
    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.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Le Blanc, Katarina
    Karolinska Inst, Ctr Hematol & Regenerat Med, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Clin Immunol, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Transfus Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Type 1 Diabetes Mellitus Donor Mesenchymal. Stromal Cells Exhibit Comparable Potency to Healthy Controls In Vitro2016In: Stem Cells Translational Medicine, ISSN 2157-6564, E-ISSN 2157-6580, Vol. 5, no 11, 1485-1495 p.Article in journal (Refereed)
    Abstract [en]

    Bone marrow mesenchymal stromal cells (BM-MSCs) have been characterized and used in many clinical studies based on their immunomodulatory and regenerative properties. We have recently reported the benefit of autologous MSC systemic therapy in the treatment of type 1 diabetes mellitus (T1D). Compared with allogeneic cells, use of autologous products reduces the risk of eliciting undesired complications in the recipient, including rejection, immunization, and transmission of viruses and prions; however, comparable potency of autologous cells is required for this treatment approach to remain feasible. To date, no analysis has been reported that phenotypically and functionally characterizes MSCs derived from newly diagnosed and late-stage T1D donors in vitro with respect to their suitability for systemic immunotherapy. In this study, we used gene array in combination with functional in vitro assays to address these questions. MSCs from T1D donors and healthy controls were expanded from BM aspirates. BM mononuclear cell counts and growth kinetics were comparable between the groups, with equivalent colony-forming unit-fibroblast capacity. Gene microarrays demonstrated differential gene expression between healthy and late-stage T1D donors in relation to cytokine secretion, immunomodulatory activity, and wound healing potential. Despite transcriptional differences, T1D MSCs did not demonstrate a significant difference from healthy controls in immunosuppressive activity, migratory capacity, or hemocompatibility. We conclude that despite differential gene expression, expanded MSCs from T1D donors are phenotypically and functionally similar to healthy control MSCs with regard to their immunomodulatory and migratory potential, indicating their suitability for use in autologous systemic therapy.

  • 28.
    Domsgen, Erna
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med HS, Ctr Infect Med, S-14186 Stockholm, Sweden..
    Lind, Katharina
    Karolinska Univ Hosp, Karolinska Inst, Dept Med HS, Ctr Infect Med, S-14186 Stockholm, Sweden..
    Kong, Lingjia
    Univ Turku, Turku Ctr Biotechnol, FIN-20520 Turku, Finland.;Abo Akad Univ, FIN-20520 Turku, Finland..
    Huhn, Michael H.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med HS, Ctr Infect Med, S-14186 Stockholm, Sweden.;Astra Zeneca AB R&D, Pepparedsleden 1, S-43150 Molndal, Sweden..
    Rasool, Omid
    Univ Turku, Turku Ctr Biotechnol, FIN-20520 Turku, Finland.;Abo Akad Univ, FIN-20520 Turku, Finland..
    van Kuppeveld, Frank
    Univ Utrecht, Div Virol, Dept Infect Dis & Immunol, Fac Vet Med, NL-3584 Utrecht, Netherlands..
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lahesmaa, Riitta
    Univ Turku, Turku Ctr Biotechnol, FIN-20520 Turku, Finland.;Abo Akad Univ, FIN-20520 Turku, Finland..
    Flodstrom-Tullberg, Malin
    Karolinska Univ Hosp, Karolinska Inst, Dept Med HS, Ctr Infect Med, S-14186 Stockholm, Sweden.;Univ Tampere, Inst Biosci & Med Technol, Tampere 33520, Finland..
    An IFIH1 gene polymorphism associated with risk for autoimmunity regulates canonical antiviral defence pathways in Coxsackievirus infected human pancreatic islets2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, 39378Article in journal (Refereed)
    Abstract [en]

    The IFIH1 gene encodes the pattern recognition receptor MDA5. A common polymorphism in IFIH1 (rs1990760, A946T) confers increased risk for autoimmune disease, including type 1-diabetes (T1D). Coxsackievirus infections are linked to T1D and cause beta-cell damage in vitro. Here we demonstrate that the rs1990760 polymorphism regulates the interferon (IFN) signature expressed by human pancreatic islets following Coxsackievirus infection. A strong IFN signature was associated with high expression of IFN lambda 1 and IFN lambda 2, linking rs1990760 to the expression of type III IFNs. In the highresponding genotype, IRF-1 expression correlated with that of type III IFN, suggesting a positivefeedback on type III IFN transcription. In summary, our study uncovers an influence of rs1990760 on the canonical effector function of MDA5 in response to an acute infection of primary human parenchymal cells with a clinically relevant virus linked to human T1D. It also highlights a previously unrecognized connection between the rs1990760 polymorphism and the expression level of type III IFNs.

  • 29.
    Duprez, Ida Rasmusson
    et al.
    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.
    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.
    Preparatory studies of composite mesenchymal stem cell islets for application in intraportal islet transplantation2011In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 116, no 1, 8-17 p.Article in journal (Refereed)
    Abstract [en]

    Abstract Background. Low engraftment and adverse immune reactions hamper the success rate of clinical islet transplantation. In this study, we investigated the capacity of human mesenchymal stem cells (MSCs) to adhere to human islets of Langerhans and their effects in immune modulation and during blood interactions in vitro. Methods. Composite MSC-islets were formed by suspension co-culture, and the phenotype was evaluated by confocal microscopy. Islet function was assessed by dynamic insulin release in response to glucose in vitro. Mixed lymphocyte-islet reactions (MLIR) and the tubing blood loop model were utilized as in vitro tools to analyse the effect of MSCs on the innate and adaptive immune reactions triggered by the islets. Results. MSCs rapidly adhered to islets and spread out to cover the islet surface. Insulin expression and secretion were sustained with the MSC coating. MSC-coated islets showed unaffected reactions with blood in vitro in comparison to control islets. Furthermore, MSCs suppressed lymphocyte proliferation induced by islet cells in MLIR. Conclusion. We conclude that it is possible to create composite MSC-islets to enable delivery of the MSCs by utilizing the adhesive capacity of the MSCs. This could have beneficial immunosuppressive effects in optimizing pancreatic islet transplantation.

  • 30.
    Eich, Torsten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Estrada, Sergio
    Brandhorst, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Brandhorst, Heide
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Nilsson, Bo
    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.
    Lundgren, Torbjörn
    Positron emission tomography: A real-time tool to quantify early islet engraftment in a preclinical large animal model2007In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 84, no 7, 893-898 p.Article in journal (Refereed)
    Abstract [en]

    Background. Clinical islet transplantation is currently being explored as a therapeutic option for persons with type I diabetes and hypoglycemic unawareness. Techniques to monitor graft survival are urgently needed to optimize the procedure. Therefore, the objective of the present study was to develop a technique for imaging survival of transplanted islets in the peritransplant and early posttransplant phase.

    Methods. Isolated porcine islets were labeled in vitro with 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG) and infused intraportally into anesthetized pigs (n=10). Dynamic examination was performed on a positron emission tomography/computed tomography hybrid system.

    Results. More than 95% of the radioactivity was confined to the islets at the time of transplantation. The peak percentage of infused radioactivity within the liver, quantified at the end of the islet infusion, was only 54±5.1%. The distribution of the radioactivity in the liver was found to be heterogeneous. A whole-body examination showed no accumulation in the lungs or brain; extrahepatic radioactivity was, except urinary excretion, evenly distributed in the pig body.

    Conclusions. Our results imply that almost 50% of the islets were damaged to the extent that the FDG contained was release within minutes after intraportal transplantation. The distribution of radioactivity without accumulation in the brain indicates that the activity is released from lysed islet cells in the form of [18F]FDG-6P rather than native [18F]FDG. The presented technique shows promise to become a powerful and quantitative tool, readily available in the clinic, to evaluate initial islet engraftment and survival.

  • 31.
    Elshebani, Asma
    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, Clinical Immunology.
    Westman, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tuvemo, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Frisk, Gun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Effects on isolated human pancreatic islet cells after infection with strains of enterovirus isolated at clinical presentation of type 1 diabetes2007In: Virus Research, ISSN 0168-1702, E-ISSN 1872-7492, Vol. 124, no 1-2, 193-203 p.Article in journal (Refereed)
    Abstract [en]

    Enterovirus (EV) infections have been associated with the pathogenesis of type 1 diabetes (T1D). They may cause β-cell destruction either by cytolytic infection of the cells or indirectly by triggering the autoimmune response. Evidence for EV involvement have been presented in several studies, EV-IgM antibodies have been reported in T1D patients, EV-RNA has been found in the blood from T1D patients at onset, and EV have been isolated from newly diagnosed T1D. Our aim was to study infections with EV isolates from newly diagnosed T1D patients in human pancreatic islets in vitro. Two of them (T1 and T2) originated from a mother and her son diagnosed with T1D on the same day, the other two (A and E) were isolated from a pair of twins at the time of diagnosis of T1D in one of them. Isolated human pancreatic islets were infected and viral replication, viability and degree of cytolysis as well as insulin release in response to high glucose were measured. All four EV isolates replicated in the islet cells and virus particles and virus-induced vesicles were seen in the cytoplasm of the β-cells. The isolates varied in their ability to induce cytolysis and to cause destruction of the islets and infection with two of the isolates (T1 and A) caused more pronounced destruction of the islets. Infection with the isolate from the healthy twin boy (E) was the least cytolytic. The ability to secrete insulin in response to high glucose was reduced in all infected islets as early as 3 days post infection, before any difference in viability was observed. To conclude, strains of EV isolated from T1D patients at clinical presentation of T1D revealed β-cell tropism, and clearly affected the function of the β-cell. In addition, the infection caused a clear increase in the number of dead cells.

  • 32.
    Engstrand, Mats
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Johnsson, Cecilia
    Department of Surgical Sciences.
    Larsson, Erik
    Department of Genetics and Pathology.
    Tufveson, Gunnar
    Department of Surgical Sciences.
    Korsgren, Olle
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Quantification of lymphocytes propagating from rat-kidney allografts--a tool to monitor anti-rejection treatment.2002In: Transpl Immunol, ISSN 0966-3274, Vol. 10, no 1, 31-6 p.Article in journal (Refereed)
  • 33.
    Engstrand, Mats
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Naghibi, Mansour
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    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.
    Johnsson, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Lymphocyte propagation from biopsies of kidney allografts2006In: Transplant Immunology, ISSN 0966-3274, E-ISSN 1878-5492, Vol. 16, no 3-4, 215-219 p.Article in journal (Refereed)
    Abstract [en]

    Morphological evaluation of transplant biopsies, usually using the Banff classification, is the most important tool to diagnose rejection after kidney transplantation. However, morphological analysis only scores the amount and localisation of infiltrating cells, and studies show that up to 30% of grafts with a stable function display infiltration of lymphocytes consistent with acute cellular rejection. Methods to study the functional properties of the infiltrating lymphocytes are therefore needed. We applied a tissue culture system on biopsies from transplanted human kidneys, allowing infiltrating cells to propagate out from the tissue. Cells were then counted and subtyped by flow cytometry. The results were correlated to morphology. In total, 92 biopsies from 69 patients were analysed. For 14 patients, serial biopsies were available. In grafts with cellular or combined cellular and vascular rejection, the number of ex vivo propagated mononuclear cells was higher than from non-rejecting grafts. A similar pattern was seen for CD3(+) T cells as well as for T cells expressing CD25 or MHC class II antigens. However, the proportion of CD25(+) or MHC class II(+) T lymphocytes was similar in all groups (no rejection, vascular rejection, borderline changes, cellular rejection, combined cellular and vascular rejection). In all groups the number of CD4(+) cells was higher than the number of CD8(+) cells. The results confirm previous experimental studies showing that graft-infiltrating cells are possible to culture in vitro and that lymphocyte propagation correlates to acute cellular rejection. Tissue culturing is easy to perform and evaluate and can be used to determine and analyse the cellular immune response to allografts and may thus be used as a complement to morphological analyses.

  • 34.
    Engstrand, Mats
    et al.
    Division of Clinical Immunology and Transfusion Medicine, University Hospital, Uppsala, Sweden.
    Lidehäll, Anna Karin
    Division of Clinical Immunology and Transfusion Medicine, University Hospital, Uppsala, Sweden.
    Tötterman, Thomas H.
    Division of Clinical Immunology and Transfusion Medicine, University Hospital, Uppsala, Sweden.
    Herrman, Björn
    Division of Microbiology, University Hospital, Uppsala, Sweden.
    Eriksson, Britt-Marie
    Division of Infectious Diseases, University Hospital, Uppsala, Sweden.
    Korsgren, Olle
    Division of Clinical Immunology and Transfusion Medicine, University Hospital, Uppsala, Sweden.
    Cellular responses to cytomegalovirus in immunosuppressed patients: circulating CD8+ T cells recognizing CMVpp65 are present but display functional impairment2003In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 132, no 1, 96-104 p.Article in journal (Refereed)
    Abstract [en]

    The availability of tetrameric complexes of HLA class I molecules folded with immunodominant peptides makes it possible to utilize flow cytometry for rapid and highly specific visualization of virus specific CD8+ T cells. An alternate technique is to incubate whole blood with specific antigens and to subsequently detect and characterize responding T cells (e.g. by performing intracellular staining of interferon-gamma). By using an HLA-A2 tetramer construct folded with the same immunodominant CMV-peptide as that used for peptide pulsing, we monitored both the presence and functional capacity of CMV-specific CD8+ T cells. In addition T cell activation was assayed by determination of CD38 and CD69 expression. Twelve organ transplant patients and 31 healthy blood donors with latent CMV infection were investigated using CMV pp65 tetramer staining and intracellular staining of interferon-gamma after CMV pp65 peptide pulsing or CMV lysate pulsing. CMV-specific T cells were detected in similar absolute numbers as well as frequencies of T cells in the two groups investigated. However, the CMV-specific CD8+ T cells in immunosuppressed individuals showed a decreased functional response to the CMV-peptide, as evidenced by reduced interferon-gamma production when compared to healthy blood donors (19%; 42%, P < 0·005). In addition, CD38 expression was markedly higher in immunosuppressed patients compared to healthy blood donors (24%; 6%, P < 0·005). In a case report we demonstrate that reactivation of CMV can occur in an immunosuppressed patient with high number of CMV-specific T cells, but without functional capacity. Hence, these findings reflect impaired activation of cytotoxic T cells controlling latent CMV infection in immunosuppressed patients.

  • 35. Eriksson, B.
    et al.
    Eriksson, O.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Selvaraju, R.
    Kandeel, F.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Detection of metastatic insulinoma by positron emission tomography with [68Ga]Exendin-4-a case report2014In: Wiener Klinische Wochenschrift, ISSN 0043-5325, E-ISSN 1613-7671, Vol. 126, no S3, S152-S152 p.Article in journal (Other academic)
  • 36.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Carlsson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Blom, Elisabeth
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Preclinical evaluation of a 68Ga-labeled biotin analogue for applications in islet transplantation2012In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 39, no 3, 415-421 p.Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION:

    Islet transplantation is a promising treatment for type 1 diabetes mellitus, but the fate of the cells after intraportal infusion is unclear. It is therefore imperative to develop novel techniques for noninvasive imaging and quantification of events following islet transplantation.

    METHODS:

    Small islet-like microbeads, avidin-covered agarose resins (AARs), were used as a model system for islet transplantation. Capability for specific [(68)Ga]Ga-DOTA-(PEG)(2)-biotin uptake and retention for either AARs or human islets conjugated with avidin by means of a heparin scaffold was studied in vitro. Biodistribution of the novel positron emission tomography (PET) tracer [(68)Ga]Ga-DOTA-(PEG)(2)-biotin was evaluated in mice treated by intraportal transplantation of AARs by μPET/computed tomography and ex vivo organ distribution and compared with control mice.

    RESULTS:

    AARs had high capability to bind [(68)Ga]Ga-DOTA-(PEG)(2)-biotin, close to 50% of administrated tracer/μl in vitro (>0.25 MBq/μl). Avidin-tagged human islets could bind on average 2.2% of administered tracer/μl. Specificity (>90%) and retention (>90% after 1 h) were high for both AARs and avidin-tagged islets. Hepatic tracer uptake and retention were increased in mice transplanted with AARs [standardized uptake value (SUV)=2.6] compared to the untreated group (SUV=1.4). In vivo uptake of tracer to AARs was blocked by preadministration of unlabeled biotin.

    CONCLUSIONS:

    Avidin-tagged islet-like objects can be tracked in hepatic volume after intraportal transplantation by using [(68)Ga]Ga-DOTA-(PEG)(2)-biotin and PET.

  • 37.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Espes, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Selvaraju, Ram K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Jansson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Biglarnia, Alireza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, 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.
    The Positron Emission Tomography ligand [11C]5-Hydroxy-Tryptophan can be used as a surrogate marker for the human endocrine pancreas2014In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, no 10, 3428-3437 p.Article in journal (Refereed)
    Abstract [en]

    In humans a well-developed serotonin system is localized to the pancreatic islets while being absent in exocrine pancreas. Assessment of pancreatic serotonin biosynthesis could therefore be used to estimate the human endocrine pancreas. Proof of concept was tested in a prospective clinical trial by comparisons of type 1 diabetic (T1D) patients, with extensive reduction of beta cells, with healthy volunteers (HV).C-peptide negative (i.e. insulin-deficient) T1D subjects (n=10) and HV (n=9) underwent dynamic Positron Emission Tomography with the radiolabeled serotonin precursor [(11)C]5-Hydroxy-Tryptophan ([(11)C]5-HTP).A significant accumulation of [(11)C]5-HTP was obtained in the pancreas of the HV, with large inter-individual variation. A substantial and highly significant reduction (66%) in the pancreatic uptake of [(11)C]5-HTP in T1D subjects was observed, and this was most evident in the corpus and caudal regions of the pancreas where beta-cells normally are the major constituent of the islets.[(11)C]5-HTP retention in the pancreas was reduced in T1D compared to non-diabetic subjects. Accumulation of [(11)C]5-HTP in the pancreas of both HV and subjects with T1D were in agreement with previously reported morphological observations on the beta cell volume implying that [(11)C]5-HTP retention is a useful non-invasive surrogate marker for the human endocrine pancreas.

  • 38.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Selvaraju, Ram K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Quantitative Imaging of Serotonergic Biosynthesis and Degradation in the Endocrine Pancreas2014In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 55, no 3, 460-465 p.Article in journal (Refereed)
    Abstract [en]

    Serotonergic biosynthesis in the endocrine pancreas, of which the islets of Langerhans is the major constituent, has been implicated in insulin release and β cell proliferation. In this study, we investigated the feasibility of quantitative noninvasive imaging of the serotonergic metabolism in the pancreas using the PET tracer (11)C-5-hydroxy-l-tryptophan ((11)C-5-HTP).

    METHODS: Uptake of (11)C-5-HTP, and its specificity for key enzymes in the serotonergic metabolic pathway, was assessed in vitro (INS-1 and PANC1 cells and human islet and exocrine preparations) and in vivo (nonhuman primates and healthy and diabetic rats).

    RESULTS: In vitro tracer uptake in endocrine cells (INS-1 and human islets), but not PANC1 and exocrine cells, was mediated specifically by intracellular conversion into serotonin. Pancreatic uptake of (11)C-5-HTP in nonhuman primates was markedly decreased by inhibition of the enzyme dopa decarboxylase, which converts (11)C-5-HTP to (11)C-serotonin and increased after inhibition of monoamine oxidase-A, the main enzyme responsible for serotonin degradation. Uptake in the rat pancreas was similarly modulated by inhibition of monoamine oxidase-A and was reduced in animals with induced diabetes.

    CONCLUSION: The PET tracer (11)C-5-HTP can be used for quantitative imaging of the serotonergic system in the endocrine pancreas.

  • 39.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Sjöberg, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Biglarnia, Alireza
    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.
    Functional Imaging of the Pancreatic Graft by Positron Emission Tomography2013In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 96, no 6, S94-S94 p.Article in journal (Other academic)
  • 40.
    Eriksson, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Selvaraju, Ram K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Kandeel, Fouad
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Detection of Metastatic Insulinoma by Positron Emission Tomography with [(68)Ga]Exendin-4 -: a case report2014In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 99, no 5, 1519-1524 p.Article in journal (Refereed)
    Abstract [en]

    Context:

    Insulinomas are the most common cause of endogenous hyperinsulinaemic hypoglycaemia in non-diabetic adult patients. They are usually benign and curative surgery is the "gold standard" treatment if they can be localized. Malignant insulinomas are seen in less than 10% and their prognosis is poor. The Glucagon Like Peptide-1 receptor (GLP-1R) is markedly upregulated in insulinomas - especially benign lesions which are difficult to localize with current imaging techniques.

    Objective:

    To assess the possibility of the detection of primary and metastatic insulinoma by PET using [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 ([(68)Ga]Exendin-4) in a patient with severe hypoglycemia.

    Design:

    Dynamic and static PET/CT examination of a patient using [68Ga]Exendin-4.

    Setting:

    Uppsala University Hospital, Uppsala, Sweden.

    Patients:

    A patient presented with hypoglycemia requiring continuous intravenous glucose infusions. A pancreatic insulinoma was suspected and an exploratory laparotomy was urgently performed. At surgery, a tumor in the pancreatic tail with an adjacent metastasis was found and a distal pancreatic resection (plus splenectomy) and removal of lymph node was performed. Histopathology showed a WHO grade II insulinoma. Postoperatively hypoglycemia persisted but a PET/CT examination using the neuroendocrine marker [(11)C]-5-hydroxy-L-tryptophan was negative.

    Interventions:

    The patient was administered with [(68)Ga]Exendin-4 and examined by dynamic PET over the liver and pancreas.

    Main Outcome Measures:

    N/A

    Results:

    The stable GLP-1 analogue Exendin-4 was labeled with (68)Ga for PET imaging of GLP-1R expressing tumors. The patient was examined by [(68)Ga]Exendin-4-PET/CT which confirmed several small GLP-1R positive lesions in the liver and a lymph node that could not be conclusively identified by other imaging techniques. The results obtained from the [(68)Ga]Exendin-4-PET/CT examination provided the basis for continued systemic treatment.

    Conclusion:

    The results of the [(68)Ga]Exendin-4-PET/CT examination governed the treatment strategy of this particular patient and demonstrated the potential of this technique for future management of patients with this rare, but potentially fatal disease.

  • 41.
    Fransson, Moa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Brännström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Duprez, Ida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Le Blanc, Katarina
    Karolinska Inst, Dept Clin Immunol & Transfus Med, Huddinge, Sweden; Karolinska Univ Hosp, Hematol Ctr, Huddinge, Sweden.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Magnusson, Peetra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Mesenchymal stromal cells supportendothelial cell interactions in anintramuscular islet transplantation model2015In: Regenerative Medicine Research, ISSN 2050-490X, Vol. 3, UNSP 1Article in journal (Refereed)
    Abstract [en]

    Background:

    Mesenchymal stromal cells (MSC) have been under investigation for a number of therapies andhave lately been in focus as immunosuppressive actors in the field of transplantation. Herein we haveextended our previously published in vitro model of MSC-islets in an experimental setting of islettransplantation to the abdominal muscle.Human islets coated with luciferase-GFP transduced human MSC were transplanted to the abdomen muscletissue of NOD-scid ILR2γnull mice and cellular interactions were investigated by confocal microscopy.

    Results:

    The MSC reduced fibrotic encapsulation and facilitated endothelial cell interactions. In particular, weshow a decreased fraction of αSMA expressing fibrotic tissue surrounding the graft in presence of MSC-isletscompared to islets solely distributed into the muscle tissue. Also, in the presence of MSC, human isletendothelial cells migrated from the center of the graft out into the surrounding tissue forming chimeric bloodvessels with recipient endothelial cells. Further, in the graft periphery, MSC were seen interacting with infiltratingmacrophages.

    Conclusions:

    Here, in our experimental in vivo model of composite human islets and luciferase-GFP-transducedhuman MSC, we enable the visualization of close interactions between the MSC and the surrounding tissue. In thismodel of transplantation the MSC contribute to reduced fibrosis and increased islet endothelial cell migration.Furthermore, the MSC interact with the recipient vasculature and infiltrating macrophages.

  • 42.
    Friberg, Andrew S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hellgren, Mikko
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    A Vast Amount of Enzyme Activity Fails to Be Absorbed Within the Human Pancreas: Implications for Cost-Effective Islet Isolation Procedures2013In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 95, no 6, E36-E38 p.Article in journal (Refereed)
  • 43.
    Friberg, Andrew S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lundgren, Torbjörn
    Malm, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Felldin, M
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Jenssen, T
    Kyllonen, L
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Tibell, Annika
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Transplanted functional islet mass: donor islet preparation, and recipitent factors influence early graft function in islet-after-kidney patients2012In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 93, no 6, 632-638 p.Article in journal (Refereed)
    Abstract [en]

    Background.

    The ability to predict clinical function of a specific islet batch released for clinical transplantation using standardized variables remains an elusive goal.

    Methods.

    Analysis of 10 donor, 7 islet isolation, 3 quality control, and 6 recipient variables was undertaken in 110 islet-after-kidney transplants and correlated to the pre- to 28-day posttransplant change in C-peptide to glucose and creatinine ratio ([DELTA]CP/GCr).

    Results.

    Univariate analysis yielded islet volume transplanted (Spearman r=0.360, P<0.001) and increment of insulin secretion (r=0.377, P<0.001) as variables positively associated to [DELTA]CP/GCr. A negative association to [DELTA]CP/GCr was cold ischemia time (r=-0.330, P<0.001). A linear, backward-selection multiple regression was used to obtain a model for the transplanted functional islet mass (TFIM). The TFIM model, composed of islet volume transplanted, increment of insulin secretion, cold ischemia time, and exocrine tissue volume transplanted, accounted for 43% of the variance of the clinical outcome in the islet-after-kidney data set.

    Conclusion.

    The TFIM provides a straightforward and potent tool to guide the decision to use a specific islet preparation for clinical transplantation.

  • 44.
    Friberg, Andrew S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ståhle, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Honkanen-Scott, Minna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ingvast, Sofie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Human Islet Isolation Processing Times Shortened by One Hour: No Incubation Between Tissue Harvest and Isopycnic Islet Purification2013In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 96, no 6, S146-S146 p.Article in journal (Other academic)
  • 45. Gao, R.
    et al.
    Ustinov, J.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Otonkoski, Timo
    Effects of immunosuppressive drugs on in vitro neogenesis of human islets: mycophenolate mofetil inhibits the proliferation of ductal cells2007In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 7, no 4, 1021-1026 p.Article in journal (Refereed)
    Abstract [en]

    Assuming that neogenesis contributes to long-term function of islet grafts, it is important to study the effects of immunosuppressive drugs on precursor cell proliferation and differentiation. We examined the effects of low-dose immunosuppressive drugs on these processes in vitro. Immunosuppressive drugs, including sirolimus, tacrolimus, mycophenolate mofetil (MMF), daclizumab and their combinations were tested in parallel culture wells through either the expansion phase (5-7 days) or the entire culture period (4-5 weeks). MMF, alone or in combination with sirolimus or tacrolimus, severely hampered duct-cell proliferation by 8-fold during the expansion period, and significantly reduced the total DNA content by about 40% after 5-week culture. After 4-5 week exposure to different drugs, only sirolimus and daclizumab showed no adverse effects on insulin content, whereas significant reductions of 30-60% in insulin content were seen in all other experimental groups. Only tacrolimus decreased the insulin content per DNA, as well as the proportion of insulin-positive cells. In conclusion, MMF has a potent inhibitory effect on neogenesis primarily through an antiproliferative effect on the precursors, whereas tacrolimus mainly affects beta-cell differentiation. Sirolimus and daclizumab have no adverse effects on these parameters. The immunosuppressive protocol may be an important determinant of long-term clinical islet graft function.

  • 46. Gao, Ru
    et al.
    Ustinov, Jarkko
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Mikkola, Milla
    Lundin, Karolina
    Otonkoski, Timo
    Maturation of in vitro-generated human islets after transplantation in nude mice2007In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 264, no 1-2, 28-34 p.Article in journal (Refereed)
    Abstract [en]

    The long-term function of human pancreatic islet grafts may depend on the neogenesis of beta cells from epithelial precursors within the grafted tissue. We have developed an in vitro model for human islet neogenesis. In this study, we have investigated the morphological signs of maturation in cultivated human islet buds (CHIBs) before and after transplantation. Clusterin is a molecule associated with beta-cell differentiation in rodents. In adult human islets, clusterin expression was located only in alpha- and PP-cells, but in CHIBs and human fetal islets, it was distributed in all four types of endocrine cells. Some immature endocrine cells in the CHIBs co-expressed insulin and glucagon. After transplantation, CHIBs became mature with one type of hormone per endocrine cell, and clusterin expression became restricted in alpha-cells. Cells co-expressing endocrine markers and cytokeratin 19, as a sign of ductal to endocrine cell transition, were frequently detected in both fresh islets and CHIBs after transplantation. We conclude that clusterin may be involved in the development of islets, and the in vitro-derived islets become mature after transplantation into nude mice. Ductal cell differentiation into endocrine cells may be an important factor in sustaining the long-term function of islet transplants.

  • 47. Gao, Ru
    et al.
    Ustinov, Jarkko
    Pulkkinen, Mari-Anne
    Lundin, Karolina
    Korsgren, Olle
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Klinisk immunologi.
    Otonkoski, Timo
    Characterization of endocrine progenitor cells and critical factors for their differentiation in human adult pancreatic cell culture.2003In: Diabetes, ISSN 0012-1797, Vol. 52, no 8, 2007-15 p.Article in journal (Refereed)
  • 48.
    Goto, M
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. KITM.
    Eich, T M
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. KITM.
    Stahle, M
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. KITM.
    Malmborg, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. KITM.
    Engkvist, M
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. KITM.
    Korsgren, O
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. KITM.
    Technical improvement of human pancreatic islet isolation.2005In: Transplant Proc, ISSN 0041-1345, Vol. 37, no 2, 1313-4 p.Article in journal (Refereed)
  • 49.
    Goto, M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. KITM.
    Johansson, U
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. KITM.
    Eich, T M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. KITM.
    Lundgrem, T
    Engkvist, M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. KITM.
    Felldin, M
    Foss, A
    Kallen, R
    Salmela, K
    Tibell, A
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Nilsson, B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. KITM.
    Korsgren, O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. KITM.
    Key factors for human islet isolation and clinical transplantation.2005In: Transplant Proc, ISSN 0041-1345, Vol. 37, no 2, 1315-6 p.Article in journal (Refereed)
  • 50.
    Goto, Masafumi
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Klinisk immunologi.
    Eich, Torsten
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Klinisk immunologi.
    Felldin, M
    Foss, A
    Kallen, R
    Salmela, K
    Tibell, A
    Tufveson, G
    Department of Surgical Sciences.
    Fujimori, K
    Engkvist, Margareta
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Klinisk immunologi.
    Korsgren, Olle
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Klinisk immunologi.
    Refinement of the automated method for human islet isolation and presentation of a closed system for in vitro islet culture2004In: Transplantation, Vol. 78, 1367-1375 p.Article in journal (Refereed)
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