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  • 1.
    Abadpour, Shadab
    et al.
    Oslo University Hospital, Oslo, Norway.
    Halvorsen, Bente
    Oslo University Hospital, Oslo, Norway.
    Sahraoui, Afaf
    University of Oslo, Oslo, Norway.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Aukrust, Pål
    Oslo University Hospital, Oslo, Norway.
    Scholz, Hanne
    Oslo University Hospital, Oslo, Norway.
    Interleukin-22 reverses human islet dysfunction and apoptosis triggered by hyperglycemia and LIGHT2018In: Journal of Molecular Endocrinology, ISSN 0952-5041, E-ISSN 1479-6813, article id JME-17-0182Article in journal (Refereed)
    Abstract [en]

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

  • 2.
    Adamson, L.
    et al.
    Karolinska Inst, Dept Pathol & Oncol, Stockholm, Sweden..
    Andersson, B.
    Gothenburg Univ, Immunol, Gothenburg, Sweden..
    Kiessling, R.
    Karolinska Inst, Dept Pathol & Oncol, Stockholm, Sweden..
    Nasman-Glaser, B.
    Karolinska Inst, Dept Pathol & Oncol, Stockholm, Sweden..
    Karlsson-Parra, Alex
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    GMP-production of an allogenic DC-based cancer vaccine (INTUVAX) for treatment of patients with metastatic kidney-or primary liver cancer. Comparison of two production platforms for DC-generation2016In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 46, p. 946-947Article in journal (Other academic)
  • 3. Adamson, R. E.
    et al.
    Frazier, A. A.
    Evans, H.
    Chambers, K. F.
    Schenk, E.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Birnie, R.
    Mitry, R. R.
    Dhawan, A.
    Maitland, N. J.
    In Vitro Primary Cell Culture as a Physiologically Relevant Method for Preclinical Testing of Human Oncolytic Adenovirus2012In: Human Gene Therapy, ISSN 1043-0342, E-ISSN 1557-7422, Vol. 23, no 2, p. 218-230Article in journal (Refereed)
    Abstract [en]

    Ad[I/PPT-E1A] is an oncolytic adenovirus that specifically kills prostate cells via restricted replication by a prostate-specific regulatory element. Off-target replication of oncolytic adenoviruses would have serious clinical consequences. As a proposed ex vivo test, we describe the assessment of the specificity of Ad[I/PPT-E1A] viral cytotoxicity and replication in human nonprostate primary cells. Four primary nonprostate cell types were selected to mimic the effects of potential in vivo exposure to Ad[I/PPT-E1A] virus: bronchial epithelial cells, urothelial cells, vascular endothelial cells, and hepatocytes. Primary cells were analyzed for Ad[I/PPT-E1A] viral cytotoxicity in MTS assays, and viral replication was determined by hexon titer immunostaining assays to quantify viral hexon protein. The results revealed that at an extreme multiplicity of infection of 500, unlikely to be achieved in vivo, Ad[I/PPT-E1A] virus showed no significant cytotoxic effects in the nonprostate primary cell types apart from the hepatocytes. Transmission electron microscopy studies revealed high levels of Ad[I/PPT-E1A] sequestered in the cytoplasm of these cells. Adenoviral green fluorescent protein reporter studies showed no evidence for nuclear localization, suggesting that the cytotoxic effects of Ad[I/PPT-E1A] in human primary hepatocytes are related to viral sequestration. Also, hepatocytes had increased amounts of coxsackie adenovirus receptor surface protein. Active viral replication was only observed in the permissive primary prostate cells and LNCaP prostate cell line, and was not evident in any of the other nonprostate cells types tested, confirming the specificity of Ad[I/PPT-E1A]. Thus, using a relevant panel of primary human cells provides a convenient and alternative preclinical assay for examining the specificity of conditionally replicating oncolytic adenoviruses in vivo.

  • 4. Aeinehband, Shahin
    et al.
    Lindblom, Rickard P F
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Al Nimer, Faiez
    Vijayaraghavan, Swetha
    Sandholm, Kerstin
    Khademi, Mohsen
    Olsson, Tomas
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson, Kristina Ekdahl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Darreh-Shori, Taher
    Piehl, Fredrik
    Complement Component C3 and Butyrylcholinesterase Activity Are Associated with Neurodegeneration and Clinical Disability in Multiple Sclerosis2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 4Article in journal (Refereed)
    Abstract [en]

    Dysregulation of the complement system is evident in many CNS diseases but mechanisms regulating complement activation in the CNS remain unclear. In a recent large rat genomewide expression profiling and linkage analysis we found co-regulation of complement C3 immediately downstream of butyrylcholinesterase (BuChE), an enzyme hydrolyzing acetylcholine (ACh), a classical neurotransmitter with immunoregulatory effects. We here determined levels of neurofilament-light (NFL), a marker for ongoing nerve injury, C3 and activity of the two main ACh hydrolyzing enzymes, acetylcholinesterase (AChE) and BuChE, in cerebrospinal fluid (CSF) from patients with MS (n = 48) and non-inflammatory controls (n = 18). C3 levels were elevated in MS patients compared to controls and correlated both to disability and NFL. C3 levels were not induced by relapses, but were increased in patients with >= 9 cerebral lesions on magnetic resonance imaging and in patients with progressive disease. BuChE activity did not differ at the group level, but was correlated to both C3 and NFL levels in individual samples. In conclusion, we show that CSF C3 correlates both to a marker for ongoing nerve injury and degree of disease disability. Moreover, our results also suggest a potential link between intrathecal cholinergic activity and complement activation. These results motivate further efforts directed at elucidating the regulation and effector functions of the complement system in MS, and its relation to cholinergic tone.

  • 5. Agmon-Levin, Nancy
    et al.
    Damoiseaux, Jan
    Kallenberg, Cees
    Sack, Ulrich
    Witte, Torsten
    Herold, Manfred
    Bossuyt, Xavier
    Musset, Lucille
    Cervera, Ricard
    Plaza-Lopez, Aresio
    Dias, Carlos
    Sousa, Maria Jose
    Radice, Antonella
    Eriksson, Catharina
    Hultgren, Olof
    Viander, Markku
    Khamashta, Munther
    Regenass, Stephan
    Coelho Andrade, Luis Eduardo
    Wiik, Allan
    Tincani, Angela
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Bloch, Donald B.
    Fritzler, Marvin J.
    Chan, Edward K. L.
    Garcia-De la Torre, I.
    Konstantinov, Konstantin N.
    Lahita, Robert
    Wilson, Merlin
    Vainio, Olli
    Fabien, Nicole
    Sinico, Renato Alberto
    Meroni, Pierluigi
    Shoenfeld, Yehuda
    International recommendations for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies2014In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 73, no 1, p. 17-23Article in journal (Refereed)
    Abstract [en]

    Anti-nuclear antibodies (ANA) are fundamental for the diagnosis of autoimmune diseases, and have been determined by indirect immunofluorescence assay (IIFA) for decades. As the demand for ANA testing increased, alternative techniques were developed challenging the classic IIFA. These alternative platforms differ in their antigen profiles, sensitivity and specificity, raising uncertainties regarding standardisation and interpretation of incongruent results. Therefore, an international group of experts has created recommendations for ANA testing by different methods. Two groups of experts participated in this initiative. The European autoimmunity standardization initiative representing 15 European countries and the International Union of Immunologic Societies/World Health Organization/Arthritis Foundation/Centers for Disease Control and Prevention autoantibody standardising committee. A three-step process followed by a Delphi exercise with closed voting was applied. Twenty-five recommendations for determining ANA (1-13), anti-double stranded DNA antibodies (14-18), specific antibodies (19-23) and validation of methods (24-25) were created. Significant differences between experts were observed regarding recommendations 24-25 (p<0.03). Here, we formulated recommendations for the assessment and interpretation of ANA and associated antibodies. Notably, the roles of IIFA as a reference method, and the importance of defining nuclear and cytoplasmic staining, were emphasised, while the need to incorporate alternative automated methods was acknowledged. Various approaches to overcome discrepancies between methods were suggested of which an improved bench-to-bedside communication is of the utmost importance. These recommendations are based on current knowledge and can enable harmonisation of local algorithms for testing and evaluation of ANA and related autoantibodies. Last but not least, new more appropriate terminologies have been suggested.

  • 6.
    Ahlgren, Kerstin M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Moretti, Silvia
    Lundgren, Brita Ardesjö
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Karlsson, Iulia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Åhlin, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Norling, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hallgren, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Perheentupa, Jaakko
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Crewther, Pauline E.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Bensing, Sophie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Scott, Hamish S.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Romani, Luigina
    Lobell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model2011In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 41, no 1, p. 235-245Article in journal (Refereed)
    Abstract [en]

    Autoimmune polyendocrine syndrome type 1 (APS-1) is a multiorgan autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. Chronic mucocutaneous candidiasis, hypoparathyroidism and adrenal failure are hallmarks of the disease. The critical mechanisms causing chronic mucocutaneous candidiasis in APS-1 patients have not been identified although autoantibodies to cytokines are implicated in the pathogenesis. To investigate whether the Th reactivity to Candida albicans (C. albicans) and other stimuli was altered, we isolated PBMC from APS-1 patients and matched healthy controls. The Th17 pathway was upregulated in response to C. albicans in APS-1 patients, whereas the IL-22 secretion was reduced. Autoantibodies against IL-22, IL-17A and IL-17F were detected in sera from APS-1 patients by immunoprecipitation. In addition, Aire-deficient (Aire(0/0) ) mice were much more susceptible than Aire(+/+) mice to mucosal candidiasis and C. albicans-induced Th17- and Th1-cell responses were increased in Aire(0/0) mice. Thus an excessive IL-17A reactivity towards C. albicans was observed in APS-1 patients and Aire(0/0) mice.

  • 7.
    Ajalloueian, F.
    et al.
    Isfahan Univ Technol, Dept Text Engn, Ctr Excellence Appl Nanotechnol, Esfahan, Iran..
    Fransson, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Tavanai, H.
    Isfahan Univ Technol, Dept Text Engn, Ctr Excellence Appl Nanotechnol, Esfahan, Iran..
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Magnusson, Peetra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala Univ, Dept Immunol Genet & Pathol IGP, Uppsala, Sweden..
    Arpanaei, A.
    Natl Inst Genet Engn & Biotechnol, Dept Ind & Environm Biotechnol, Tehran, Iran..
    Comparing PLGA and PLGA/Chitosan Nanofibers Seeded by Msc: A Cell-scaffold Interaction Study2015In: Tissue Engineering. Part A, ISSN 1937-3341, E-ISSN 1937-335X, Vol. 21, p. S406-S407Article in journal (Other academic)
  • 8.
    Ajalloueian, Fatemeh
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fransson, Moa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Tavanai, Hossein
    Massuni, Mohammad
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    LeBlanc, Katarina
    Arpanaei, Ayyoob
    Magnusson, Peetra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Investigation of Human Mesenchymal Stromal Cells Cultured on PLGA orPLGA/Chitosan Electrospun Nanofibers2015In: Journal of Bioprocessing & Biotechniques, ISSN 2155-9821, Vol. 5, no 6, article id 230Article in journal (Refereed)
    Abstract [en]

    We compared the viability, proliferation, and differentiation of human Mesenchymal Stromal Cells (MSC)after culture on poly(lactic-co-glycolic acid) (PLGA) and PLGA/chitosan (PLGA/CH) hybrid scaffolds. We appliedconventional and emulsion electrospinning techniques, respectively, for the fabrication of the PLGA and PLGA/CH scaffolds. Electrospinning under optimum conditions resulted in an average fiber diameter of 166 ± 33 nmfor the PLGA/CH and 680 ± 175 nm for the PLGA scaffold. The difference between the tensile strength of thePLGA and PLGA/CH nanofibers was not significant, but PLGA/CH showed a significantly lower tensile modulusand elongation at break. However, it should be noted that the extensibility of the PLGA/CH was higher than thatof the nanofibrous scaffolds of pure chitosan. As expected, a higher degree of hydrophilicity was seen with PLGA/CH, as compared to PLGA alone. The biocompatibility of the PLGA and PLGA/CH scaffolds was compared usingMTS assay as well as analysis by scanning electron microscopy and confocal microscopy. The results showed thatboth scaffold types supported the viability and proliferation of human MSC, with significantly higher rates on PLGA/CH nanofibers. Nonetheless, an analysis of gene expression of MSC grown on either PLGA or PLGA/CH showed asimilar differentiation pattern towards bone, nerve and adipose tissues.

  • 9. Almgren, J.
    et al.
    Lindvall, P.
    Englund,
    Norda, Rut
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lubenow, Norbert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Safwenberg, J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Comparison of Three Fully Automated Systems for Immunohematology with the Focus on Two Important Aspects of Capacity-Efficiency and Stress2014In: Transfusion, ISSN 0041-1132, E-ISSN 1537-2995, Vol. 54, p. 173A-174AArticle in journal (Other academic)
  • 10.
    Anagandula, Mahesh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Studies of Enterovirus Infection and Induction of Innate Immunity in Human Pancreatic Cells2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Several epidemiological and clinical studies have indicated a possible role of Enterovirus (EV) infection in type 1 diabetes (T1D) development. However, the exact casual mechanism of these viruses in T1D development is not known. The aim of this thesis is to study various EVs that have been shown to differ in their immune phenotype, lytic ability, association with induction of islet autoantibodies, ability to replicate, cause islet disintegration and induce innate antiviral pathways in infected pancreatic cells in vitro. Furthermore, EV presence and pathogenic process in pancreatic tissue and isolated islets of T1D patients was also studied.

    Studies in this thesis for first time show the detection of EV RNA and protein in recent onset live T1D patients supporting the EV hypothesis in T1D development. Further all EV serotypes studied were able to replicate in islets, causing variable amount of islet disintegration ranging from extensive islet disintegration to not affecting islet morphology at all. However, one of the EV serotype replicated in only two out of seven donors infected, highlighting the importance of individual variation between donors. Further, this serotype impaired the insulin response to glucose stimulation without causing any visible islet disintegration, suggesting that this serotype might impaired the insulin response by inducing a functional block. Infection of human islets with the EV serotypes that are differentially associated with the development of islet autoantibodies showed the islet cell disintegration that is comparable with their degree of islet autoantibody seroconversion. Suggesting that the extent of the epidemic-associated islet autoantibody induction may depend on the ability of the viral serotypes to damage islet cells. Furthermore, one of the EV strains showed unique ability to infect and replicate both in endo and exocrine cells of the pancreas. EV replication in both endo and exocrine cells affected the genes involved in innate and antiviral pathways and induction of certain genes with important antiviral activity significantly varied between different donors. Suggesting that the same EV infection could result in different outcome in different individuals. Finally, we compared the results obtained by lytic and non lytic EV strains in vitro with the findings reported in fulminant and slowly progressing autoimmune T1D and found some similarities. In conclusion the results presented in this thesis further support the role of EV in T1D development and provide more insights regarding viral and host variation.  This will improve our understanding of the possible causative mechanism by EV in T1D development.

    List of papers
    1. Detection of a low-grade enteroviral infection in the islets of Langerhans of living patients newly diagnosed with type 1 diabetes
    Open this publication in new window or tab >>Detection of a low-grade enteroviral infection in the islets of Langerhans of living patients newly diagnosed with type 1 diabetes
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    2015 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, no 5, p. 1682-1687Article in journal (Refereed) Published
    Abstract [en]

    The Diabetes Virus Detection study (DiViD) is the first to examine fresh pancreatic tissue at the diagnosis of type 1 diabetes for the presence of viruses. Minimal pancreatic tail resection was performed 3-9 weeks after onset of type 1 diabetes in 6 adult patients (age 24-35 years). The presence of enteroviral capsid protein 1 (VP1) and the expression of class I HLA were investigated by immunohistochemistry. Enterovirus RNA was analyzed from isolated pancreatic islets and from fresh frozen whole pancreatic tissue using PCR and sequencing. Non-diabetic organ donors served as controls. VP1 was detected in the islets of all type 1 diabetes patients (2 of 9 controls). Hyperexpression of class I HLA molecules was found in the islets of all patients (1 of 9 controls). Enterovirus specific RNA sequences were detected in 4 of 6 cases (0 of 6 controls). The results were confirmed in different laboratories. Only 1.7 % of the islets contained VP1 positive cells and the amount of enterovirus RNA was low. The results provides evidence for the presence of enterovirus in pancreatic islets of type 1 diabetic patients, being consistent with the possibility that a low grade enteroviral infection in the pancreatic islets contribute to disease progression in humans.

    National Category
    Endocrinology and Diabetes Microbiology
    Identifiers
    urn:nbn:se:uu:diva-239513 (URN)10.2337/db14-1370 (DOI)000353431200023 ()25422108 (PubMedID)
    Available from: 2014-12-29 Created: 2014-12-29 Last updated: 2017-12-05
    2. 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 Pathway
    Open this publication in new window or tab >>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 Pathway
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    2014 (English)In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 86, no 8, p. 1402-1411Article in journal (Refereed) Published
    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.

    Keywords
    enterovirus, type 1 diabetes, innate immunity, human pancreatic islets, RNA sensors
    National Category
    Infectious Medicine Microbiology
    Identifiers
    urn:nbn:se:uu:diva-231113 (URN)10.1002/jmv.23835 (DOI)000339486200015 ()24249667 (PubMedID)
    Available from: 2014-09-05 Created: 2014-09-04 Last updated: 2017-12-05
    3. Expression of Innate Immunity Genes and Damage of Primary Human Pancreatic Islets by Epidemic Strains of Echovirus: Implication for Post-Virus Islet Autoimmunity
    Open this publication in new window or tab >>Expression of Innate Immunity Genes and Damage of Primary Human Pancreatic Islets by Epidemic Strains of Echovirus: Implication for Post-Virus Islet Autoimmunity
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    2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 11, p. e77850-Article in journal (Refereed) Published
    Abstract [en]

    Three large-scale Echovirus (E) epidemics (E4, E16, E30), each differently associated to the acute development of diabetes related autoantibodies, have been documented in Cuba. The prevalence of islet cell autoantibodies was moderate during the E4 epidemic but high in the E16 and E30 epidemic. The aim of this study was to evaluate the effect of epidemic strains of echovirus on beta-cell lysis, beta-cell function and innate immunity gene expression in primary human pancreatic islets. Human islets from non-diabetic donors (n = 7) were infected with the virus strains E4, E16 and E30, all isolated from patients with aseptic meningitis who seroconverted to islet cell antibody positivity. Viral replication, degree of cytolysis, insulin release in response to high glucose as well as mRNA expression of innate immunity genes (IFN-b, RANTES, RIG-I, MDA5, TLR3 and OAS) were measured. The strains of E16 and E30 did replicate well in all islets examined, resulting in marked cytotoxic effects. E4 did not cause any effects on cell lysis, however it was able to replicate in 2 out of 7 islet donors. Beta-cell function was hampered in all infected islets (P<0.05); however the effect of E16 and E30 on insulin secretion appeared to be higher than the strain of E4. TLR3 and IFN-beta mRNA expression increased significantly following infection with E16 and E30 (P<0.033 and P<0.039 respectively). In contrast, the expression of none of the innate immunity genes studied was altered in E4-infected islets. These findings suggest that the extent of the epidemic-associated islet autoimmunity may depend on the ability of the viral strains to damage islet cells and induce pro-inflammatory innate immune responses within the infected islets.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-212334 (URN)10.1371/journal.pone.0077850 (DOI)000326499300010 ()
    Available from: 2013-12-10 Created: 2013-12-09 Last updated: 2017-12-06Bibliographically approved
    4. Field strains of Echovirus 6 infect human endocrine and exocrine pancreatic cells and induce pro-inflammatory innate immune responses.
    Open this publication in new window or tab >>Field strains of Echovirus 6 infect human endocrine and exocrine pancreatic cells and induce pro-inflammatory innate immune responses.
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    (English)Article in journal (Refereed) In press
    Abstract [en]

    Increasing evidence suggests that type 1 diabetes (T1D) is a combined endocrine-exocrine disease. Human enteroviruses (HEV) have been suggested to induce T1D, but so far evidence on HEV infection in human pancreas has been reported only in islets and ductal cells. Aim of this study was to investigate the capability of HEV strains to infect primary human endocrine and exocrine pancreatic cells and to induce the expression of innate immunity genes in both cell types. Isolated human pancreatic islets and exocrine cells were either mock-infected or inoculated with seven field isolates of Echovirus 6 (E6). Beta-cell tropic strains of E4, E16 and E30 were assayed in primary exocrine cells. Viral infection, replication, virus-induced cytopathic effect (CPE) and expression of innate immunity genes were measured. All the seven strains of E6 replicated in both pancreatic endocrine and exocrine cells with infectious progeny production and appearance of CPE. By contrast, no virus titer increase or CPE were observed in exocrine cells exposed to E4, E16 and E30. Virus particles were found in E6-infected acinar cells, both free in cytoplasm and enclosed in vacuoles. Insulin granules accumulation in proximity to virus particles and beta cells functional impairment were demonstrated in E6-infected islets. Endocrine and exocrine cells responded to E6 infection by upregulating the transcription of genes involved in viral recognition (IF1H1), antiviral defense (OAS1, IFN-β) and inflammation (CXCL10, CCL5). Our results indicate that islets and exocrine pancreatic cells productively support the E6 infection and suggest that HEV-associated T1D may involve both endocrine and exocrine pancreas.

    National Category
    Clinical Medicine Microbiology
    Identifiers
    urn:nbn:se:uu:diva-283276 (URN)
    Available from: 2016-04-12 Created: 2016-04-12 Last updated: 2016-06-01
    5. Gene expression analysis of human islets in a subject at onset of type 1 diabetes
    Open this publication in new window or tab >>Gene expression analysis of human islets in a subject at onset of type 1 diabetes
    Show others...
    2014 (English)In: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 51, no 2, p. 199-204Article in journal (Refereed) Published
    Abstract [en]

    Swollen islet cells have been repeatedly described at onset of type 1 diabetes, but the underlying mechanism of this observation, termed hydropic degeneration, awaits characterization. In this study, laser capture microdissection was applied to extract the islets from an organ donor that died at onset of type 1 diabetes and from an organ donor without pancreatic disease. Morphologic analysis revealed extensive hydropic degeneration in 73 % of the islets from the donor with type 1 diabetes. Expression levels of genes involved in apoptosis, ER stress, beta cell function, and inflammation were analyzed in isolated and laser-captured islets by qPCR. The chemokine MCP-1 was expressed in islets from the donor with type 1 diabetes while undetectable in the control donor. No other signs of inflammation were detected. There were no signs of apoptosis on the gene expression level, which was also confirmed by negative immunostaining for cleaved caspase-8. There was an increased expression of the transcription factor ATF4, involved in transcription of ER stress genes, in the diabetic islets, but no further signs of ER stress were identified. In summary, on the transcription level, islets at onset of type 1 diabetes in which many beta cells display hydropic degeneration show no obvious signs of apoptosis, ER stress, or inflammation, supporting the notion that these cells are responding normally to high glucose and eventually succumbing to beta cell exhaustion. Also, this study validates the feasibility of performing qPCR analysis of RNA extracted from islets from subjects with recent onset of T1D and healthy controls by laser capture microdissection.

    National Category
    Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-202844 (URN)10.1007/s00592-013-0479-5 (DOI)000334054200004 ()23624551 (PubMedID)
    Available from: 2013-06-28 Created: 2013-06-28 Last updated: 2017-12-06Bibliographically approved
    6. Enterovirus-induced changes in explanted human islet of Langerhans resemble findings in islets of fulminant and conventional type 1 diabetes
    Open this publication in new window or tab >>Enterovirus-induced changes in explanted human islet of Langerhans resemble findings in islets of fulminant and conventional type 1 diabetes
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Hypothesis: Fulminant Type 1 diabetes is a unique subtype of T1D, mostly reported in the Japanese population, which is characterized by extensive beta cell death already at onset, often without any insulitis. Enterovirus (EV) infections are associated with the etiology of both fulminant and conventional T1D. However the causative mechanism is not known for any of these diseases. EVs capability to cause lytic vs non-lytic infection in explanted human islets may have implications on the pathogenesis of these two types of T1D.

    Aim: To study the effect of infection of explanted human pancreatic islets with lytic (CBV-1) and non-lytic (CBV-4) Coxsackie B virus strains on cytopathic effect/islet disintegration and to what extent genes involved in viral sensing, antiviral defense and encoding of islet auto-antigens are affected by the viral replication. Also, to compare these findings with the findings reported in fulminant and conventional T1D.

    Methods: Degree of cytopathic effect/islet disintegration was studied and viral replication was measured. Genes involved in viral sensing (NOD2, TLR7 and TLR4), antiviral pathways (OAS2, MX1, PKR, and IRF7), genes coding for known islet auto antigens (GAD65, ZNT8) and the islet hormones, insulin and glucagon, were studied. Mock-infected explanted islet served as controls.

    Results: All CBV strains replicated in the explanted islets but only the CBV-1 strains caused cytopathic effect/islet cell disintegration. Infection with all CBV strains resulted in the induction of genes encoding OAS2 and MX1. In contrast, mRNA expression levels of the gene encoding insulin was reduced. The gene encoding PKR was induced by one of the lytic strains (CBV-1-11) and also by the non-lytic CBV4 strain, while the mRNA expression levels of genes encoding glucagon, NOD2, TLR7, TLR4, MCL1, GAD65 and ZNT8 were not significantly affected.

    National Category
    Endocrinology and Diabetes Microbiology
    Identifiers
    urn:nbn:se:uu:diva-283281 (URN)
    Available from: 2016-04-12 Created: 2016-04-12 Last updated: 2016-06-01
  • 11.
    Anagandula, Mahesh
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hyöty, Heikki
    University of Tampere, School of Medicine, Tampere, Finland ,Fimlab Ltd, Pirkanmaa Hospital District, Finland.
    Frisk, Gun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Enterovirus-induced changes in explanted human islet of Langerhans resemble findings in islets of fulminant and conventional type 1 diabetesManuscript (preprint) (Other academic)
    Abstract [en]

    Hypothesis: Fulminant Type 1 diabetes is a unique subtype of T1D, mostly reported in the Japanese population, which is characterized by extensive beta cell death already at onset, often without any insulitis. Enterovirus (EV) infections are associated with the etiology of both fulminant and conventional T1D. However the causative mechanism is not known for any of these diseases. EVs capability to cause lytic vs non-lytic infection in explanted human islets may have implications on the pathogenesis of these two types of T1D.

    Aim: To study the effect of infection of explanted human pancreatic islets with lytic (CBV-1) and non-lytic (CBV-4) Coxsackie B virus strains on cytopathic effect/islet disintegration and to what extent genes involved in viral sensing, antiviral defense and encoding of islet auto-antigens are affected by the viral replication. Also, to compare these findings with the findings reported in fulminant and conventional T1D.

    Methods: Degree of cytopathic effect/islet disintegration was studied and viral replication was measured. Genes involved in viral sensing (NOD2, TLR7 and TLR4), antiviral pathways (OAS2, MX1, PKR, and IRF7), genes coding for known islet auto antigens (GAD65, ZNT8) and the islet hormones, insulin and glucagon, were studied. Mock-infected explanted islet served as controls.

    Results: All CBV strains replicated in the explanted islets but only the CBV-1 strains caused cytopathic effect/islet cell disintegration. Infection with all CBV strains resulted in the induction of genes encoding OAS2 and MX1. In contrast, mRNA expression levels of the gene encoding insulin was reduced. The gene encoding PKR was induced by one of the lytic strains (CBV-1-11) and also by the non-lytic CBV4 strain, while the mRNA expression levels of genes encoding glucagon, NOD2, TLR7, TLR4, MCL1, GAD65 and ZNT8 were not significantly affected.

  • 12.
    Anagandula, Mahesh
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Richardson, Sarah J.
    University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, UK.
    Oberste, M. Steven
    Centers for Disease Control and Prevention, Atlanta, Georgia.
    Sioofy-Khojine, Amir-Babak
    School of Medicine, University of Tampere, Tampere, Finland.
    Hyoty, Heikki
    School of Medicine, University of Tampere, Tampere, Finland ,Fimlab Ltd, Pirkanmaa Hospital District, Finland.
    Morgan, Noel G.
    University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, UK.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Frisk, Gun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Infection of Human Islets of Langerhans With Two Strains of Coxsackie B Virus Serotype 1: Assessment of Virus Replication, Degree of Cell Death and Induction of Genes Involved in the Innate Immunity Pathway2014In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 86, no 8, p. 1402-1411Article in journal (Refereed)
    Abstract [en]

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

  • 13. Arlestig, Lisbeth
    et al.
    Brink, Mikael
    Hansson, Monika
    Jakobsson, Per Johan
    Holmdahl, Rikard
    Mathsson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Klareskog, Lars
    Rantapaa-Dahlqvist, Solbritt M.
    Single Nucleotide Polymorphisms within the HLA-DRB1 Gene in Relation to Antibodies Against Citrullinated Peptides in Individuals Prior to the Development of Rheumatoid Arthritis2012In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no S10, p. S180-S180Article in journal (Other academic)
  • 14.
    Asif, Sana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ekdahl, Kristina N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Fromell, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Gustafson, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Paediatric Surgery.
    Barbu, Andreea
    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.
    Le Bland, Katarina
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Teramura, Yuji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Heparinization of cell surfaces with short pepetide-conjugated PEG-lipid regulates thromboinflammation in thransplantation of human MSCs and hepatocytes2016In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 35, p. 194-205Article in journal (Refereed)
    Abstract [en]

    Infusion of therapeutic cells into humans is associated with immune responses, including thromboinflammation, which result in a large loss of transplanted cells\ To address these problems, heparinization of the cell surfaces was achieved by a cell-surface modification technique using polyethylene glycol conjugated phospholipid (PEG-lipid) derivatives. A short heparin-binding peptide was conjugated to the PEG-lipid for immobilization of heparin conjugates on the surface of human mesenchymal stem cells (hMSCs) and human hepatocytes. Here three kinds of heparin-binding peptides were used for immobilizing heparin conjugates and examined for the antithrombogenic effects on the cell surface. The heparinized cells were incubated in human whole blood to evaluate their hemocompatibility by measuring blood parameters such as platelet count, coagulation markers, complement markers, and Factor Xa activity. We found that one of the heparin-binding peptides did not show cytotoxicity after the immobilization with heparin conjugates. The degree of binding of the heparin conjugates on the cell surface (analyzed by flow cytometer) depended on the ratio of the active peptide to control peptide. For both human MSCs and hepatocytes in whole-blood experiments, no platelet aggregation was seen in the heparin conjugate-immobilized cell group vs. the controls (non-coated cells or control peptide). Also, the levels of thrombin-antithrombin complex (TAT), C3a, and sC5b-9 were significantly lower than those of the controls, indicating a lower activation of coagulation and complement. Factor Xa analysis indicated that the heparin conjugate was still active on the cell surface at 24 h post-coating. It is possible to immobilize heparin conjugates onto hMSC and human hepatocyte surfaces and thereby protect the cell surfaces from damaging thromboinflammation. Statement of Signigficance We present a promising approach to enhance the biocompatibility of therapeutic cells. Here we used short peptide-conjugated PEG-lipid for cell surface modification and heparin conjugates for the coating of human hepatocytes and MSCs. We screened the short peptides to find higher affinity for heparinization of cell surface and performed hemocompatibility assay of heparinized human hepatocytes and human MSCs in human whole blood. Using heparin-binding peptide with higher affinity, not only coagulation activation but also complement activation was significantly suppressed. Thus, it was possible to protect human hepatocytes and human MSCs from the attack of thromboinflammatory activation, which can contribute to the improvement graft survival.

  • 15.
    Asif, Sana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Jonsson, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Linnaeus Univ, Linnaeus Ctr Biomat Chem, Kalmar, Sweden..
    Teramura, Yuji
    Univ Tokyo, Dept Bioengn, Tokyo, Japan..
    Gustafson, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Paediatric Surgery.
    Ekdahl, Kristina N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Linnaeus Univ, Linnaeus Ctr Biomat Chem, Kalmar, Sweden..
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Conjugation of human recombinant CD39 to primary human hepatocytes protects against thromboinflammation2015In: Xenotransplantation, ISSN 0908-665X, E-ISSN 1399-3089, Vol. 22, p. S87-S87Article in journal (Other academic)
  • 16.
    Asif, Sana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Jonsson, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Linnaeus Univ, Linnaeus Ctr Biomat Chem, Kalmar, Sweden..
    Teramura, Yuji
    Univ Tokyo, Dept Bioengn, Tokyo, Japan..
    Gustafson, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Paediatric Surgery.
    Ekdahl, Kristina N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Linnaeus Univ, Linnaeus Ctr Biomat Chem, Kalmar, Sweden..
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Conjugation Of Human Recombinant CD39 To Primary Human Hepatocytes Protects Against Thromboinflammation2015In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 99, no 11, p. S140-S140Article in journal (Other academic)
  • 17.
    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, p. 959-967Article in journal (Refereed)
    Abstract [en]

    Background:

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

    Methods:

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

    Results:

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

    Conclusions:

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

  • 18.
    Asif, Sana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Teramura, Yuji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Bohlin, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Magnusson, Peetra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Design of a Biocompatible Extracorporeal Device for Applying Islets of Langerhans as a Bio-Artificial Pancreas2013In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 96, no 6, p. S69-S69Article in journal (Other academic)
  • 19.
    Asif, Sana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Teramura, Yuji
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Biglarnia, Alireza
    Protective role of PEG conjugated phospholipid in reducing ischemic reperfusion injury in an en bloc allogeneic pig kidney transplant model2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, p. 121-121Article in journal (Other academic)
  • 20.
    Azuma, Tomoyuki
    et al.
    Univ Tokyo, Dept Bioengn, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138656, Japan..
    Teramura, Yuji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Univ Tokyo, Dept Bioengn, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138656, Japan.
    Hoshi, Toru
    Nihon Univ, Dept Mat & Appl Chem, Coll Sci & Technol, Tokyo 1018308, Japan..
    Takai, Madoka
    Univ Tokyo, Dept Bioengn, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138656, Japan..
    Enhancement of Cell Adhesion on a Phosphorylcholine-Based Surface through the Interaction with DNA Mediated by Ca2+ Ions2016In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 120, no 48, p. 12272-12278Article in journal (Refereed)
    Abstract [en]

    2-Methacryloyloxyethyl phosphorylcholine (MPC) has a PC group and is one of the most well-known bioinert polymers. In this study, we evaluated the interaction between MPC and DNA, which specifically interacts with the phospholipid head group via Ca2+ ions. A MPC monolayer and poly(MPC) brush were fabricated to observe the effect of the structure on the interaction between MPC and DNA via Ca2+ ions. The poly(MPC) brush, which shows higher MPC unit density, more efficiently interacted with DNA via Ca2+ ions. Also, serum protein could interact with the poly(MPC) brush via DNA, although the brush itself hardly interacted with serum proteins. Cell adhesion was significantly provoked on poly(MPC)/DNA compared with poly(MPC) because serum protein adsorption was induced on poly(MPC)/DNA.

  • 21.
    Azuma, Tomoyuki
    et al.
    Univ Tokyo, Dept Bioengn, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138656, Japan..
    Teramura, Yuji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Univ Tokyo, Dept Bioengn, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138656, Japan..
    Takai, Madoka
    Univ Tokyo, Dept Bioengn, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138656, Japan..
    Cellular Response to Non-contacting Nanoscale Sublayer: Cells Sense Several Nanometer Mechanical Property2016In: ACS Applied Materials and Interfaces, ISSN 1944-8244, E-ISSN 1944-8252, Vol. 8, no 17, p. 10710-10716Article in journal (Refereed)
    Abstract [en]

    Cell adhesion is influenced not only from the surface property of materials but also from the mechanical properties of the nanometer sublayer just below the surface. In this study, we fabricated a well-defined diblock polymer brush composed of 2-methacryloyloxyethyl phosphorylcholine (MPC) and 2-aminoethyl methacrylate (AEMA). The underlying layer of poly(MPC) is a highly viscous polymer, and the surface layer of poly(AEMA) is a cell-adhesive cationic polymer. The adhesion of L929 mouse fibroblasts was examined on the diblock polymer brush to see the effect of a non contacting underlying polymer layer on the cell-adhesion behavior. Cells could sense the viscoelasticity of the underlying layers at the nanometer level, although the various fabricated diblock polymer brushes had the same surface property and the functional group. Thus, we found a new factor which could control cell spread at the nanometer level, and this insight would be important to design nanoscale biomaterials and interfaces.

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

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

  • 23.
    Baecklund, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Backlin, C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Toes, R
    Huizinga, Twj
    Åhlin, E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Askling, J
    Hochberg, F H
    Klareskog, L
    Kay, J
    Smedby, K E
    Anti-cyclic citrullinated peptide antibodies, other common autoantibodies, and smoking as risk factors for lymphoma in patients with rheumatoid arthritis2018In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Patients with rheumatoid arthritis (RA) are at increased risk of lymphoma. There is no biomarker to indicate future lymphoma risk in RA and it is not known whether factors associated with an increased risk of RA also confer an increased risk of lymphoma. We investigated whether anti-cyclic citrullinated peptide (CCP) antibodies, other autoantibodies, and smoking, are associated with lymphoma development in RA.

    METHOD: subclasses of anti-CCP antibodies and for 15 antinuclear antibody (ANA)-associated specific autoantibodies. Relative risks were estimated as crude and adjusted odds ratios (adjOR) with 95% confidence intervals (CIs) using logistic regression.

    RESULTS: We found no association between anti-CCP IgG ≥ 25 units/mL (adjOR 1.4, 95% CI 0.7-2.7), anti-CCP IgG ≥ 500 units/mL (adjOR 1.4, 95% CI 0.7-3.0), anti-CCP Ig of other isotypes, other autoantibodies (adjOR any vs none 0.6, 95% CI 0.3-1.2), or cigarette smoking (adjOR ever vs never 1.1, 95% CI 0.5-2.2) and lymphoma risk among patients with RA.

    CONCLUSION: , IgM, or IgA), nor other common autoantibodies, nor smoking predicted lymphoma risk in RA.

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

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

  • 25.
    Barbu, Andreea
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hamad, Osama A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    The role of complement factor C3 in lipid metabolism2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, p. 101-107Article, review/survey (Refereed)
    Abstract [en]

    Abundant reports have shown that there is a strong relationship between C3 and C3a-desArg levels, adipose tissue, and risk factors for cardiovascular disease, metabolic syndrome and diabetes. The data indicate that complement components, particularly C3, are involved in lipid metabolism. The C3 fragment, C3a-desArg, functions as a hormone that has insulin-like effects and facilitates triglyceride metabolism. Adipose tissue produces and regulates the levels of complement components, which promotes generation of inflammatory initiators such as the anaphylatoxins C3a and C5a. The anaphylatoxins trigger a cyto/chemokine response in proportion to the amount of adipose tissue present, and induce inflammation and mediate metabolic effects such as insulin resistance. These observations support the concept that complement is an important participant in lipid metabolism and in obesity, contributing to the metabolic syndrome and to the low-grade inflammation associated with obesity.

  • 26.
    Bartlett, Stephen T.
    et al.
    Univ Maryland, Sch Med, Dept Surg, Baltimore, MD 21201 USA..
    Markmann, James F.
    Massachusetts Gen Hosp, Div Transplantat, Boston, MA 02114 USA..
    Johnson, Paul
    Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hering, Bernhard J.
    Univ Minnesota, Dept Surg, Schulze Diabet Inst, Box 242 UMHC, Minneapolis, MN 55455 USA..
    Scharp, David
    Prodo Labs LLC, Irvine, CA USA.;Scharp Lacy Res Inst, Irvine, CA USA..
    Kay, Thomas W. H.
    St Vincents Hosp, St Vincents Inst Med Res, Dept Med, Fitzroy, Vic 3065, Australia.;Univ Melbourne, Melbourne, Vic 3010, Australia..
    Bromberg, Jonathan
    Massachusetts Gen Hosp, Div Transplantat, Boston, MA 02114 USA..
    Odorico, Jon S.
    Univ Wisconsin, Dept Surg, Sch Med & Publ Hlth, Div Transplantat, Madison, WI USA..
    Weir, Gordon C.
    Joslin Diabet Ctr, Boston, MA 02215 USA.;Harvard Univ, Sch Med, Boston, MA USA..
    Bridges, Nancy
    NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA..
    Kandaswamy, Raja
    Univ Minnesota, Dept Surg, Schulze Diabet Inst, Box 242 UMHC, Minneapolis, MN 55455 USA..
    Stock, Peter
    Univ San Francisco, Med Ctr, Div Transplantat, San Francisco, CA 94117 USA..
    Friend, Peter
    Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Gotoh, Mitsukazu
    Fukushima Med Univ, Dept Surg, Fukushima, Japan..
    Cooper, David K. C.
    Univ Pittsburgh, Thomas E Starzl Transplantat Inst, Pittsburgh, PA USA..
    Park, Chung-Gyu
    Seoul Natl Univ, Coll Med, Dept Biomed Sci, Xenotransplantat Res Ctr,Dept Microbiol & Immunol, Seoul, South Korea..
    O'Connell, Phillip
    Univ Sydney, Westmead Hosp, Westmead Millennium Inst, Ctr Transplant & Renal Res, Westmead, NSW 2145, Australia..
    Stabler, Cherie
    Univ Miami, Sch Med, Diabet Res Inst, Coral Gables, FL 33124 USA..
    Matsumoto, Shinichi
    Natl Ctr Global Hlth & Med, Tokyo, Japan.;Otsuka Pharmaceut Factory Inc, Naruto, Japan..
    Ludwig, Barbara
    Tech Univ Dresden, Dept Med 3, D-01062 Dresden, Germany.;Tech Univ Dresden, Univ Clin Carl Gustav Carus, Helmholtz Ctr, Paul Langerhans Inst Dresden, Dresden, Germany.;DZD German Ctr Diabet Res, Dresden, Germany..
    Choudhary, Pratik
    Kings Coll London, Weston Educ Ctr, Diabet Res Grp, London WC2R 2LS, England..
    Kovatchev, Boris
    Univ Virginia, Ctr Diabet Technol, Charlottesville, VA USA..
    Rickels, Michael R.
    Univ Penn, Dept Med, Perelman Sch Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA..
    Sykes, Megan
    Coulmbia Univ, Med Ctr, Columbia Ctr Translat Immunol, New York, NY USA..
    Wood, Kathryn
    Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Kraemer, Kristy
    NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA..
    Hwa, Albert
    Juvenile Diabet Res Fdn, New York, NY USA..
    Stanley, Edward
    Murdoch Childrens Res Inst, Parkville, Vic, Australia.;Monash Univ, Melbourne, Vic 3004, Australia..
    Ricordi, Camillo
    Univ Miami, Sch Med, Diabet Res Inst, Coral Gables, FL 33124 USA..
    Zimmerman, Mark
    BetaLogics, Raritan, NJ USA..
    Greenstein, Julia
    Juvenile Diabet Res Fdn, Discovery Res, New York, NY USA..
    Montanya, Eduard
    Univ Barcelona, Hosp Univ Bellvitge, CIBERDEM, Bellvitge Biomed Res Inst IDIBELL, Barcelona, Spain..
    Otonkoski, Timo
    Univ Helsinki, Childrens Hosp, Helsinki, Finland.;Univ Helsinki, Biomedicum Stem Cell Ctr, Helsinki, Finland..
    Report from IPITA-TTS Opinion Leaders Meeting on the Future of beta-Cell Replacement2016In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 100, p. S1-S44Article in journal (Refereed)
  • 27.
    Basu, Alex
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Hong, Jaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ferraz, Natalia
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Hemocompatibility of Ca2+-Crosslinked Nanocellulose Hydrogels: Toward Efficient Management of Hemostasis2017In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 17, no 11, article id 1700236Article in journal (Refereed)
    Abstract [en]

    The present work investigates Ca2+-crosslinked nanofibrillated cellulose hydrogels as potential hemostatic wound dressings by studying core interactions between the materials and a central component of wounds and wound healing—the blood. Hydrogels of wood-derived anionic nanofibrillated cellulose (NFC) and NFC hydrogels that incorporate kaolin or collagen are studied in an in vitro whole blood model and with platelet-free plasma assays. The evaluation of thrombin and factor XIIa formation, platelet reduction, and the release of activated complement system proteins, shows that the NFC hydrogel efficiently triggered blood coagulation, with a rapid onset of clot formation, while displaying basal complement system activation. By using the NFC hydrogel as a carrier of kaolin, the onset of hemostasis is further boosted, while the NFC hydrogel containing collagen exhibits blood activating properties comparable to the anionic NFC hydrogel. The herein studied NFC hydrogels demonstrate great potential for being part of advanced wound healing dressings that can be tuned to target certain wounds (e.g., strongly hemorrhaging ones) or specific phases of the wound healing process for optimal wound management.

  • 28. Behr-Gross, M. -E
    et al.
    Heiden, M.
    Norda, Rut
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Contributions of the Council of Europe's Blood Transfusion Steering Committee to the determination of rules for the selection of donors of blood and blood components and the study of sexual behaviors having an impact on blood safety2013In: Transfusion Clinique et Biologique, ISSN 1246-7820, E-ISSN 1953-8022, Vol. 20, no 2, p. 127-138Article in journal (Refereed)
    Abstract [en]

    In November 2009, the Council of Europe's Blood Transfusion Steering Committee created a group of experts to explore the problem of behaviors having an impact on the management of donors of blood and blood components and on blood transfusion safety in Europe. This ad hoc group sought a harmonised interpretation of temporary exclusion (or temporary deferral), as opposed to permanent exclusion (or permanent deferral), in the context of the selection of donors of blood and blood components. It was also given the mandate to assess, on the basis of available data, the possibility of differentiating "at risk" behaviours from behaviours "at high risk" of contamination by serious infectious diseases transmitted by blood, blood components or derived therapeutic products. The primary objective of this work was to ensure the safety of blood, blood components and derived therapeutic products for future recipients by promoting a risk analysis-based approach, given that some countries envisaged amending their provisions for donor selection. However, a risk analysis can only be performed on groups, not individuals, which may give the impression of a discriminatory approach, so it needed to be justified in the context of transfusion safety. A collaborative project, which included an investigation phase, led to the drafting of a technical memorandum that summarised the data collected in ten Council of Europe member states on the selection criteria for blood donors and the epidemiology of infectious diseases (with a focus on human immunodeficiency virus) in the general population and among blood donors. The technical memorandum was published in 2011 on the European Directorate for the Quality of Medicines and Healthcare website dedicated to this project. A draft resolution of the Committee of Ministers of the Council of Europe was then developed by the Council of Europe's Blood Transfusion Steering Committee. This text was circulated among member and observer states of the Council of Europe for review and comments.

  • 29.
    Bengtsson, Mats
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Street, J.
    Johnson, J.
    Harvey, C.
    Corbin, S.
    Darke, C.
    A new HLA-A*03 null allele - A*03:162N caused by an exon 4 insertion and discovered during an external quality assessment exercise2014In: Tissue Antigens, ISSN 0001-2815, E-ISSN 1399-0039, Vol. 83, no 1, p. 53-+Article in journal (Other academic)
  • 30.
    Berglund, David
    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.
    Preparatory Studies to Introduce Regulatory T Cells in Clinical Transplantation2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Solid organ transplantation has evolved from being an experimental procedure to a life-saving treatment for patients with end-stage organ failure. The risk of losing a transplant due to acute rejection is very low with the use of modern immunosuppressive protocols and the short-term results are impressive. However, long-term outcomes are suboptimal and transplant recipients are at increased risks for severe complications such as cancers, opportunistic infections and cardiovascular events. The previous struggle to achieve short-term survival has turned into a search for new strategies to improve patient and transplant longevity.

    Regulatory T cells (TRegs), a subset of T cells, occur naturally in the immune system and have the capacity to down regulate immune responses. Under normal conditions they maintain self-tolerance and prevent excessive immune activation. Functional TReg defects lead to a massive autoimmune response and are not compatible with life. Preclinical data support that TRegs can be used as a cell therapy to prevent transplant rejection, with the potential to minimize the need for traditional immunosuppression and improve the long-term outcome.

    This thesis aims to enhance the translation of TReg cell therapy to clinical organ transplantation. In particular, strategies for isolation and expansion of TRegs from uremic patients awaiting kidney transplantation have been assessed. A non-invasive imaging technique to study T cell products after intravenous administration was developed, for use in future clinical trials. The performance of a novel cell purification technique was investigated to potentially improve the clinical production of TRegs.

    The thesis demonstrates that TRegs can be isolated and expanded from uremic patients to display potent suppressive properties in vitro. The mode of isolation and expansion affect the functional characteristics, where cells purified with cytometry based techniques and expanded with mature dendritic cells were the most advantageous. T cells can be labeled using the radioactive tracer [111In]oxine with preserved viability and subsequently followed in vivo with SPECT/CT for more than 1 week after intravenous administration. The use of microfluidic switch technology offers a novel way of purifying TRegs at high speed, purity and viability, under conditions compatible with clinical use.

    List of papers
    1. Isolation, expansion and functional assessment of CD4+CD25+FoxP3+ regulatory T cells and Tr1 cells from uremic patients awaiting kidney transplantation
    Open this publication in new window or tab >>Isolation, expansion and functional assessment of CD4+CD25+FoxP3+ regulatory T cells and Tr1 cells from uremic patients awaiting kidney transplantation
    Show others...
    2012 (English)In: Transplant Immunology, ISSN 0966-3274, E-ISSN 1878-5492, Vol. 26, no 1, p. 27-33Article in journal (Refereed) Published
    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.

    National Category
    Immunology in the medical area
    Identifiers
    urn:nbn:se:uu:diva-170517 (URN)10.1016/j.trim.2011.09.003 (DOI)000300203800004 ()
    Available from: 2012-03-13 Created: 2012-03-12 Last updated: 2018-01-12Bibliographically approved
    2. Obtaining regulatory T cells from uraemic patients awaiting kidney transplantation for use in clinical trials
    Open this publication in new window or tab >>Obtaining regulatory T cells from uraemic patients awaiting kidney transplantation for use in clinical trials
    Show others...
    2013 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 173, no 2, p. 310-322Article in journal (Refereed) Published
    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.

    National Category
    Surgery
    Identifiers
    urn:nbn:se:uu:diva-199952 (URN)10.1111/cei.12112 (DOI)000321287500016 ()23607776 (PubMedID)
    Available from: 2013-05-17 Created: 2013-05-17 Last updated: 2017-12-06Bibliographically approved
    3. Imaging the in vivo fate of human T cells following transplantation in immunoincompetent mice - Implications for clinical cell therapy trials
    Open this publication in new window or tab >>Imaging the in vivo fate of human T cells following transplantation in immunoincompetent mice - Implications for clinical cell therapy trials
    Show others...
    2013 (English)In: Transplant Immunology, ISSN 0966-3274, E-ISSN 1878-5492, Vol. 29, no 1-4, p. 105-108Article in journal (Refereed) Published
    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. 

    Keywords
    T cell, In vivo imaging, Cell therapy, SPECT/CT
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-216763 (URN)10.1016/j.trim.2013.09.009 (DOI)000329145600018 ()
    Available from: 2014-01-24 Created: 2014-01-24 Last updated: 2017-12-06Bibliographically approved
    4. Purification of regulatory T cells with the use of a fully enclosed high-speed microfluidic system
    Open this publication in new window or tab >>Purification of regulatory T cells with the use of a fully enclosed high-speed microfluidic system
    Show others...
    2014 (English)In: Cytotherapy, ISSN 1465-3249, E-ISSN 1477-2566, Vol. 16, no 10, p. 1384-1389Article in journal (Refereed) Published
    Abstract [en]

    Background aims. Despite promising advances in cellular therapies, it will be difficult to fully test or implement new therapies until advances are made in the processes for cell preparation. This study describes the use of an advanced prototype of a flow-cytometry cell purification system constructed for operation in a clinical environment to prepare regulatory T cells defined as CD4(+)/CD25(bright)/CD127(neg/low). Methods. The sort performance of the Gigasort system was directly compared with available droplet sorters using mixtures of highly fluorescent and non-fluorescent 5-mu m polystyrene particles. CD4(+)-enriched cell preparations were processed with the use of a sterile, disposable fluid handling unit with a chip containing parallel microfluidic-based sorters. Results. Similar purity and sort efficiency as found with droplet sorters were obtained with the 24-channel chip sorter system. Starting with 450 million fresh peripheral blood mononuclear cells, 150,000 to 1.7 million cells that were, on average, 85% FoxP3-positive and 97% viable, were obtained in <4 h. Conclusions. This study presents a technology adapted to regulatory requirements for clinical cell purification and that achieves high throughput and cell-friendly conditions by use of a microfluidic chip with 24 parallel microsorters, providing a rapid, sterile method of purifying regulatory T cells accurately and with excellent viability.

    National Category
    Immunology in the medical area
    Identifiers
    urn:nbn:se:uu:diva-220872 (URN)10.1016/j.jcyt.2014.05.016 (DOI)000342396800007 ()
    Available from: 2014-03-21 Created: 2014-03-21 Last updated: 2018-01-11Bibliographically approved
  • 31.
    Berglund, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Karlsson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Biglarnia, Ali-Reza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Lorant, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Carlsson, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Obtaining regulatory T cells from uraemic patients awaiting kidney transplantation for use in clinical trials2013In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 173, no 2, p. 310-322Article in journal (Refereed)
    Abstract [en]

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

  • 32.
    Berglund, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Karlsson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Palanisamy, Senthilkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Carlsson, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Imaging the in vivo fate of human T cells following transplantation in immunoincompetent mice - Implications for clinical cell therapy trials2013In: Transplant Immunology, ISSN 0966-3274, E-ISSN 1878-5492, Vol. 29, no 1-4, p. 105-108Article in journal (Refereed)
    Abstract [en]

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

  • 33.
    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.
    Kinch, Amelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Edman, Elin
    Halmstad Hospital.
    Backlin, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Pauksens, Karlis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Expression of Intratumoral Forkhead Box Protein 3 in Posttransplant Lymphoproliferative Disorders: Clinical Features and Survival Outcomes2015In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 99, no 5, p. 1036-1042Article in journal (Refereed)
    Abstract [en]

    Background. The infiltration of regulatory T cells (Tregs) in lymphomas is associated with better prognosis for some types of lymphomas, but knowledge of their role in posttransplant lymphoproliferative disorders (PTLDs) is limited. We therefore investigated the association between the expression of the Treg marker forkhead box protein 3 (FoxP3) in biopsies of PTLDs and survival, PTLD subtype, and clinical characteristics.

    Methods. Seventy-four cases of PTLD after solid organ transplantation with sufficient material for further analysis were included from a population-based study of PTLDs in Sweden. The PTLD biopsies were reevaluated and stained with the 236A/E7 antibody to detect FoxP3 in lymphoma tissue. Detailed clinical data were collected retrospectively from medical records.

    Results. Based on a cutoff level of 29 FoxP3+ cells per mm2, most (80%) of the PTLDs were FoxP3-. Forty-seven of 74 PTLDs displayed no FoxP3+ cells at all. The frequency of FoxP3+ cells did not influence median overall survival. The FoxP3- PTLDs were more frequently of T-cell phenotype (P=0.04), located at the graft (P=0.03), occurred earlier after transplantation (P=0.04), were more likely to develop in lung recipients (P=0.04), and in patients that had received anti T-cell globulin as induction therapy (P=0.02). The FoxP3+ PTLDs were associated with hepatitis C seropositivity (P=0.03). In multivariate analysis, B-cell PTLD and hepatitis C infection were independent predictors of FoxP3 positivity.

    Conclusion. Our findings suggest that intratumoral FoxP3+ Tregs do not influence survival in patients with PTLD. FoxP3+ Tregs are rare in PTLD, possibly because of heavy immunosuppression.

  • 34.
    Berglund, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lorant, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Schneider, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Carlsson, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Isolation, expansion and functional assessment of CD4+CD25+FoxP3+ regulatory T cells and Tr1 cells from uremic patients awaiting kidney transplantation2012In: Transplant Immunology, ISSN 0966-3274, E-ISSN 1878-5492, Vol. 26, no 1, p. 27-33Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 35.
    Berglund, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lindvall, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lubenow, Norbert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Green plasma2015In: Transfusion, ISSN 0041-1132, E-ISSN 1537-2995, Vol. 55, no 2, p. 245-245Article in journal (Other academic)
  • 36.
    Berglund, E.
    et al.
    Karolinsk Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Ljungdahl, M. Andersen
    Karolinsk Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Bogdanovic, D.
    Karolinsk Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Wadström, J.
    Karolinsk Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Weissenbacher, A.
    Innsbruck Med Univ, Ctr Operat Med, Innsbruck, Austria..
    Petruzzo, P.
    Hop Edouard Herriot, Dept Transplantat, Lyon, France..
    Schneeberger, S.
    Innsbruck Med Univ, Ctr Operat Med, Innsbruck, Austria..
    Clinical Significance of Alloantibodies in Hand Transplantation: Impact on Rejection and Functional Outcome2017In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 17, no S3, p. 240-240, article id 96Article in journal (Other academic)
  • 37.
    Berglund, Erik
    et al.
    Karolinska Univ Hosp, Dept Transplantat Surg, Stockholm, Sweden..
    Ljungdahl, Mette Andersen
    Karolinska Univ Hosp, Dept Transplantat Surg, Stockholm, Sweden..
    Bogdanovic, Darko
    Karolinska Univ Hosp, Dept Transplantat Surg, Stockholm, Sweden..
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Wadstrom, Jonas
    Karolinska Univ Hosp, Dept Transplantat Surg, Stockholm, Sweden..
    Weissenbacher, Anne-Marie
    Univ Oxford, Churchill Hosp, Oxford Transplant Ctr, Nuffield Dept Surg Sci, Oxford, England..
    Petruzzo, Palmina
    Hop Edouard Herriot, HCL, Dept Transplantat, Lyon, France..
    Schneeberger, Stefan
    Innsbruck Med Univ, Dept Visceral Transplant & Thorac Surg, Ctr Operat Med, Innsbruck, Austria..
    Clinical Significance Of Alloantibodies In Hand Transplantation - A Multicenter Study2017In: Transplant International, ISSN 0934-0874, E-ISSN 1432-2277, Vol. 30, p. 163-163Article in journal (Other academic)
  • 38.
    Berglund, Erik
    et al.
    Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Div Transplantat Surg, Stockholm, Sweden..
    Sellberg, Felix
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Assessing the purity of regulatory T cells: A humble reminder2017In: Cytotherapy, ISSN 1465-3249, E-ISSN 1477-2566, Vol. 19, no 2, p. 329-332Article in journal (Refereed)
  • 39. Bergman, I. -M
    et al.
    Edman, K.
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Rosengren, K. J.
    Edfors, I.
    Extensive polymorphism in the porcine Toll-like receptor 10 gene2012In: International Journal of Immunogenetics, ISSN 1744-3121, Vol. 39, no 1, p. 68-76Article in journal (Refereed)
    Abstract [en]

    The great importance of the Toll-like receptors (TLRs) in innate immunity is well established, but one family member TLR10 remains elusive. TLR10 is expressed in various tissues in several species, but its ligand is not known and its function is still poorly understood. The open reading frame of TLR10 was sequenced in 15 wild boars, representing three populations, and in 15 unrelated domestic pigs of Hampshire, Landrace and Large White origin. Amino acid positions corresponding to detected nonsynonymous single nucleotide polymorphisms (SNPs) were analysed in the crystal structures determined for the human TLR1TLR2lipopeptide complex and the human TLR10 Toll/Interleukin 1 receptor (TIR) dimer. SNP occurrence in wild boars and domestic pigs was compared, and haplotypes for the TLR10 gene and the TLR6-1-10 gene cluster were reconstructed. Despite the limited number of animals sequenced in the present study (N = 30), a larger number of SNPs were found in TLR10 than recently reported for TLR1, TLR6 and TLR2. Thirty-three SNPs were detected, of which 20 were nonsynonymous. The relative frequency of nonsynonymous (dN) and synonymous (dS) SNPs between wild boars and domestic pigs was higher in TLR10 than recently reported for TLR1, TLR6 and TLR2. However, the polymorphism reported in the present study seems to leave the function of the TLR10 molecule unaffected. Furthermore, no nonsynonymous SNPs were detected in the part of the gene corresponding to the hinge region of the receptor, probably reflecting rigorously acting functional constraint. The total number of SNPs and the number of nonsynonymous SNPs were significantly lower (P < 0.05) in the wild boars than in the domestic pigs, and fewer TLR10 haplotypes were present in the wild boars. The majority of the TLR6-1-10 haplotypes were specific for either wild boars or domestic pigs, probably reflecting differences in microbial environment and population history.

  • 40. Bergman, I. -M
    et al.
    Sandholm, K.
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Okumura, N.
    Uenishi, H.
    Guldbrandtsen, B.
    Essler, S. E.
    Knoll, A.
    Heegaard, P. M. H.
    Edfors, I.
    Juul-Madsen, H. R.
    MBL1 genotypes in wild boar populations from Sweden, Austria, the Czech Republic, and Japan2013In: INT J IMMUNOGENET, ISSN 1744-3121, Vol. 40, no 2, p. 131-139Article in journal (Refereed)
    Abstract [en]

    The single nucleotide polymorphism (SNP) G949T in the mannose-binding lectin ( MBL ) 1 gene has been associated with low MBL-A concentration in serum and detected at different frequencies in various European pig populations. However, the origin of this SNP is not known. Part of the MBL1 gene was sequenced in 12 wild boar/Large White crossbred pigs from the second backcross (BC 2) generation in a family material originating from two wild boar x Large White intercrosses. Also, MBL-A serum concentration was measured in the entire BC 2 generation (n=45). Furthermore, the genotypes of 68 wild boars from Sweden, Austria, the Czech Republic, and Japan were determined in regard to five previously described SNPs in MBL1 . The T allele of G949T was present among the BC 2 animals. MBL-A serum concentration in the BC 2 animals showed a bimodal distribution, with one-third of the animals at levels between 0.7 and 1.6gmL1 and the remaining pigs at levels around 13gmL1. There was a co-variation between the presence of the T allele and low MBL-A concentration in serum. The genotyping of the wild boars revealed differences between populations. The T allele of G949T was not detected in the Austrian and Japanese samples and is thus unlikely to be an original feature of wild boars. In contrast, it was present at high frequency (0.35) among the Swedish wild boars, probably representing a founder effect. Five MBL1 haplotypes were resolved. Only two of these were present among the Japanese wild boars compared to four in each of the European populations. This difference may reflect differences in selection pressure and population history.

  • 41. Bergseth, Grethe
    et al.
    Ludviksen, Judith K.
    Kirschfink, Michael
    Giclas, Patricia C.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Mollnes, Tom E.
    An international serum standard for application in assays to detect human complement activation products2013In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 56, no 3 SI, p. 232-239Article, review/survey (Refereed)
    Abstract [en]

    The importance of the complement system in clinical medicine has become evident during the last decades and complement therapeutics has now reached the clinic. Thus, there is an increased interest in and need for assays to evaluate complement activity and dysfunction. Pathologically increased complement activation can indirectly be evaluated by quantification of complement components, but in order to exactly measure such activation, assays for quantification of products formed during activation are required. Progress in this field is hampered by lack of standardization. Therefore, members of the International Complement Standardization Committee, a joint initiative of the International Complement Society and the International Union of Immunological Societies (IUIS), prepared a defined standard for application in assays for complement activation products. We here report on the production and properties of this International Complement Standard #2 (ICS#2). ICS#2 was made from a pool of sera from healthy blood donors (ICS#1) that was activated with a combination of heat-aggregated IgG and zymosan, and subsequently stabilized by adding EDTA and nafamostat mesylate. The protocol was optimized to make the standard applicable in the following activation product assays: C1rs-C1-inhibitor complexes, C4a, C4bc, C4d, Bb, C3bBbP, C3a, C3bc, C3dg, C5a and the soluble terminal C5b-9 complement complex (SC5b-9, TCC). ICS#2 was defined as containing 1000 complement activation units (CAU)/mL for all activation products measured. All activation products were stable after 10 times thawing and freezing and most of the activation products were stable during storage at 4 degrees C for up to 21 days. ICS#2 was produced large-scale and is considered a valuable tool for standardization, calibration and reference control for complement activation assays, providing the necessary prerequisite for quality assessments between complement laboratories. 

  • 42.
    Bergström, Marcus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Joly, A. -L
    Seiron, P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Isringhausen, S.
    Modig, E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Andersson, J.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Immunological Profiling of Haemodialysis Patients and Young Healthy Individuals with Implications for Clinical Regulatory T Cell Sorting2015In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 81, no 5, p. 318-324Article in journal (Refereed)
    Abstract [en]

    With the increasing interest in clinical trials with regulatory T cells (Tregs), immunological profiling of prospective target groups and standardized procedures for Treg isolation are needed. In this study, flow cytometry was used to assess peripheral blood lymphocyte profiles of young healthy individuals and patients undergoing haemodialysis treatment. Tregs obtained from the former may be used in haematopoietic stem cell transplantation and Tregs from the latter in the prevention of kidney transplant rejection. FOXP3 mRNA expression with accompanying isoform distribution was also assessed by the quantitative reverse transcriptase polymerase chain reaction. Flow-cytometric gating strategies were systematically analysed to optimize the isolation of Tregs. Our findings showed an overall similar immunological profile of both cohorts in spite of great differences in both age and health. Analysis of flow-cytometric gating techniques highlighted the importance of gating for both CD25high and CD127low expression in the isolation of FOXP3-positive cells. This study provides additional insight into the immunological profile of young healthy individuals and uraemic patients as well as in-depth analysis of flow-cytometric gating strategies for Treg isolation, supporting the development of Treg therapy using cells from healthy donors and uraemic patients.

  • 43.
    Berntson, Lillemor
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Nordal, Ellen
    Fasth, Anders
    Aalto, Kristiina
    Herlin, Troels
    Nielsen, Susan
    Rygg, Marite
    Zak, Marek
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Anti-type II collagen antibodies, anti-CCP, IgA RF and IgM RF are associated with joint damage, assessed eight years after onset of juvenile idiopathic arthritis (JIA)2014In: Pediatric Rheumatology, ISSN 1546-0096, E-ISSN 1546-0096, Vol. 12, p. 22-Article in journal (Refereed)
    Abstract [en]

    Background: Early appearance of antibodies specific for native human type II collagen (anti-CII) characterizes an early inflammatory and destructive phenotype in adults with rheumatoid arthritis (RA). The objective of this study was to investigate the occurrence of anti-CII, IgM RF, IgA RF and anti-CCP in serum samples obtained early after diagnosis, and to relate the occurrence of autoantibodies to outcome after eight years of disease in children with juvenile idiopathic arthritis (JIA). Methods: The Nordic JIA database prospectively included JIA patients followed for eight years with data on remission and joint damage. From this database, serum samples collected from 192 patients, at a median of four months after disease onset, were analysed for IgG anti-CII, IgM RF, IgA RF and IgG anti-CCP. Joint damage was assessed based on Juvenile Arthritis Damage Index for Articular damage (JADI-A), a validated clinical instrument for joint damage. Results: Elevated serum levels of anti-CII occurred in 3.1%, IgM RF in 3.6%, IgA RF in 3.1% and anti-CCP in 2.6% of the patients. Occurrence of RF and anti-CCP did to some extent overlap, but rarely with anti-CII. The polyarticular and oligoarticular extended categories were overrepresented in patients with two or more autoantibodies. Anti-CII occurred in younger children, usually without overlap with the other autoantibodies and was associated with high levels of C-reactive protein (CRP) early in the disease course. All four autoantibodies were significantly associated with joint damage, but not with active disease at the eight-year follow up. Conclusions: Anti-CII, anti-CCP, IgA RF and IgM RF detected early in the disease course predicted joint damage when assessed after eight years of disease. The role of anti-CII in JIA should be further studied.

  • 44.
    Biglarnia, Ali-Reza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Bennet, William
    Nilsson, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Magnusson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Yamamoto, Shinji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Lorant, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Sedigh, Amir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    von Zur-Mühlen, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Bäckman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Utilization of Small Pediatric Donors Including Infants for Pancreas and Kidney Transplantation: Exemplification of the Surgical Technique and the Surveillance2014In: Annals of Surgery, ISSN 0003-4932, E-ISSN 1528-1140, Vol. 260, no 2, p. e5-7Article in journal (Refereed)
  • 45.
    Biglarnia, Ali-Reza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson Ekdahl, Kristina
    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.
    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.
    Wadström, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Desensitization With Antigen-Specific Immunoadsorption Interferes With Complement in ABO-Incompatible Kidney Transplantation2012In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 93, no 1, p. 87-92Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Complement activation was characterized during and after desensitization treatment in 19 consecutive patients receiving ABO-incompatible (ABOi) living donor kidney transplants to assess the effect of desensitization protocol including antigen-specific immunoadsorption (IA) on complement activation.

    METHODS:

    All patients received rituximab- and tacrolimus-based triple treatment. Anti-A/B antibodies were removed by IA. Serial determinations of C3, C3a, the C3a/C3 ratio, and sC5b-9 were carried out between day -30 and postoperative day 30. C1q was measured on day -30 and the day before the transplantation. In two recipients, eluates from immunoadsorbent columns were analyzed for C3a, C1q, and immunoglobulins by western blotting. Same complement analysis was performed in eluate from a control column after in vitro perfusion of AB-plasma.

    RESULTS:

    Patient and graft survival were 100% for a median follow-up of 40 months (range, 12-60 months). There were no humoral rejections based on ABO-antigen-antibody interactions. C3a and the C3a/C3 ratio declined with the start of IA treatment, and this decline was maintained postoperatively. C1q declined from day -30 to a lower value on the day before transplantation (P<0.05). In eluates from both patient and control, immunoadsorbent column immunoglobulins together with C3a and C1q were detected.

    CONCLUSIONS:

    The current protocol including antigen-specific IA interferes with the complement system; this effect may be partially responsible for the absence of humoral rejection resulting from ABO-antigen-antibody interactions and the excellent outcomes obtained after ABO-incompatible kidney transplantation.

  • 46.
    Biglarnia, Ali-Reza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    von Zur-Mühlen, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Wagner, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Berne, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Wanders, Alkwin
    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.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Prompt reversal of a severe complement activation by eculizumab in a patient undergoing intentional ABO-incompatible pancreas and kidney transplantation2011In: Transplant International, ISSN 0934-0874, E-ISSN 1432-2277, Vol. 24, no 8, p. e61-e66Article in journal (Refereed)
    Abstract [en]

    We describe the presumably first intentional ABO-incompatible deceased-donor kidney and pancreas transplantation with a severe antibody-mediated rejection during a rebound of isoagglutinins. Rejection was successfully treated with eculizumab, which inhibits the terminal pathway of complement. Complement analysis (C3, C3d,g, and a modified assay of classical complement-related hemolytic function) documented complement activation and confirmed that eculizumab completely blocked complement function. At 6 months, the patient had normal kidney and pancreas function, and histological evaluations revealed no evidence of sustained graft damage. This successful transplantation suggests that ABO barriers can safely be overcome without extensive preconditioning, when the complement inhibitor eculizumab is included.

  • 47.
    Biglarnia, Ali-Reza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Nilsson, Kristina Ekdahl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Complement Interception Across Humoral Incompatibility in Solid Organ Transplantation: A Clinical Perspective2015In: IMMUNE RESPONSES TO BIOSURFACES: MECHANISMS AND THERAPEUTIC INTERVENTIONS, 2015, p. 211-233Conference paper (Refereed)
    Abstract [en]

    The humoral barrier in transplant biology is the result of preformed donor-specific antibodies (DSAs), directed either against human leukocyte antigens (HLA) or non-HLA antigens such as blood group (ABO) molecules. The term "sensitization" applies to patients carrying these antibodies. Transplantation is widely accepted as a life-saving opportunity for patients with terminal end-organ disease. However, in sensitized patients, transplant outcome is hampered by antibody-mediated rejection (AMR) as a consequence of DSA exposure. Furthermore, sensitized patients have limited access to "matched" organs from the both living and deceased donor pool. Considering the crucial role of the complement system in the pathophysiology of AMR and the availability of complement intervention therapeutics, there is a growing interest in complement-targeting strategies. This review highlights the emerging importance of monitoring and modulation of the complement system in the context of enabling transplantation across humoral incompatibility in sensitized recipients with preformed anti-HLA or natural anti-ABO antibodies. It also discusses the significance of the complement system in the induction of accommodation and further emphasizes current and future perspectives of novel complement therapeutics.

  • 48.
    Biglarnia, Alireza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Yamamoto, Shinji
    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. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Drachenberg, Cinthia
    Univ Maryland Hosp, Dept Pathol, Baltimore, MD 21201 USA..
    Wagner, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Sund, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    von Zur-Muehlen, Bengt
    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.
    Impact of duodenal cuff inflammation on outcome after clinical pancreas transplantation - a survey of a comprehensive follow-up strategy including serial protocol biopsy of the duodenal cuff2015In: Xenotransplantation, ISSN 0908-665X, E-ISSN 1399-3089, Vol. 22, p. S15-S15Article in journal (Other academic)
  • 49.
    Biglarnia, AliReza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Yamamoto, Shinji
    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.
    Drachenberg, Cinthia
    Univ Maryland Hosp, Dept Pathol, Baltimore, MD 21201 USA..
    Wagner, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Sund, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    von Zur-Mühlen, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Impact Of Duodenal Cuff Inflammation On Outcome After Clinical Pancreas Transplantation - A Survey Of A Comprehensive Follow-Up Strategy Including Serial Protocol Biopsy Of The Duodenal Cuff.2015In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 99, no 11, p. S24-S24Article in journal (Other academic)
  • 50.
    Blom, Kristin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    ElShafie, Amir Ibrahim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Alribat Univ Hosp, Dept Clin Pathol & Microbiol, Khartoum, Sudan.
    Jönsson, Ulla-Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Håkansson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    The genetically determined production of the alarmin eosinophil-derived neurotoxin is reduced in visceral leishmaniasis2018In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 126, no 1, p. 85-91Article in journal (Refereed)
    Abstract [en]

    Visceral leishmaniasis (VL) is the most severe form of leishmaniasis. Recent findings indicate that dendritic cells have a key role in the defense against the Leishmania parasite and that the activity of this cell may be modified by the eosinophil secretory protein eosinophil-derived neurotoxin (EDN). We hypothesized that the interactions between dendritic cells and EDN might be of importance in the disease development. Cellular content of EDN was analyzed by ELISA. The single-nucleotide polymorphisms at positions 405, 416, and 1122 in the EDN gene were analyzed by real-time PCR with TaqMan((R)) reagents. The study cohorts comprised 239 Sudanese subjects (65 healthy controls and 174 with VL) and 300 healthy Swedish controls. The eosinophil content of EDN was lower in VL as compared with controls (p < 0.0001). The EDN405 (G>C) genotype distribution was similar among Swedish and Sudanese controls, whereas VL subjects had a higher prevalence of the EDN405-GG genotype (p < 0.0001). The content of EDN in the eosinophils was closely linked to the EDN405 polymorphism (p = 0.0002). Our findings suggest that the predisposition to acquire VL is related to the genetic polymorphism of the EDN gene and the reduced production by the eosinophil of this gene product.

1234567 1 - 50 of 687
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