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  • 51. Koh, Angela
    et al.
    Senior, Peter
    Salam, Abdul
    Kin, Tatsuya
    Imes, Sharleen
    Dinyari, Parastoo
    Malcolm, Andrew
    Toso, Christian
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Shapiro, A. M. James
    Insulin-heparin infusions peritransplant substantially improve single-donor clinical islet transplant success2010In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 89, no 4, p. 465-471Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Successful islet transplantation can result in insulin independence in many patients with type 1 diabetes mellitus, but it often requires more than one islet infusion. The ability to achieve insulin independence with a single donor is an important goal in clinical islet transplantation due to the limited organ supply. METHODS: We examined factors that may be associated with insulin independence after islet transplantation with islets from a single donor, using univariate and multivariate analysis. RESULTS: Thirteen of 85 (15.3%) achieved insulin independence after single-donor islet transplantation. Using multivariate analysis, only the use of insulin and heparin infusions peritransplant was a significant factor associated with insulin independence, with an adjusted odds ratio of 8.6 (95% confidence interval 2.0-37.0). Patients who had received insulin and heparin infusions peritransplant had greater indices of islet engraftment and a greater reduction in insulin use (80.1% + or - 4.3% vs. 54.2% + or - 2.8%, P<0.001) even if insulin independence was not achieved. CONCLUSIONS: Peritransplant intensive insulin and heparin enhances islet transplantation outcomes likely related in part to mitigation of the effects of the instant blood-mediated inflammatory reaction, combined with islet rest and avoidance of inflammation. It would be important to further investigate the effects of peritransplant insulin and heparin infusions on islet engraftment.

  • 52.
    Korsgren, Erik
    et al.
    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.
    Glucose Effectiveness: The Mouse Trap in the Development of Novel beta-Cell Replacement Therapies2016In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 100, no 1, p. 111-115Article in journal (Refereed)
    Abstract [en]

    Background Cure of diabetes and normalization of glucose disposal during intravenous glucose tolerance tests (IVGTT) remains critical for stringent evaluation of novel replacement therapies in type 1 diabetes. Glucose disposal during an IVGTT depends on a complex interaction of both insulin-dependent and -independent mechanisms. Glucose effectiveness, that is, the function of glucose per se, independent of insulin, to stimulate its uptake and suppress endogenous glucose production is less recognized. Methods To unravel the relative importance of these pathways, rats were injected with streptozotocin to induce diabetes and implanted subcutaneously with slow-release devices of insulin. Results These animals demonstrated rapid normalization of blood glucose and perfectly normal glucose disposal during an IVGTT with no differences when compared with nondiabetic controls even though no active c-peptide secretion was detected in plasma and almost no remaining insulin-producing cells were present in the pancreas. Conclusions The present study highlights that glucose is the predominant mediator of its own disposal in rodents having only basal and nonglucose-regulated plasma insulin levels. The herein presented results calls for a reassessment how results obtained in the most commonly used experimental models should be interpreted in the development of future replacement therapies in type 1 diabetes.

  • 53. Kraemer, Bernhard K.
    et al.
    Klinger, Marian
    Vitko, Stefan
    Glyda, Maciej
    Midtvedt, Karsten
    Stefoni, Sergio
    Citterio, Franco
    Pietruck, Frank
    Squifflet, Jean-Paul
    Segoloni, Giuseppe
    Krueger, Bernd
    Sperschneider, Heide
    Banas, Bernhard
    Bäckman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Weber, Markus
    Carmellini, Mario
    Perner, Ferenc
    Claesson, Kerstin
    Marcinkowski, Wojciech
    Ostrowski, Marek
    Senatorski, Grzegorz
    Nordstrom, Johan
    Salmela, Kaija
    Tacrolimus-Based, Steroid-Free Regimens in Renal Transplantation: 3-Year Follow-Up of the ATLAS Trial2012In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 94, no 5, p. 492-498Article in journal (Refereed)
    Abstract [en]

    Background. Long-term use of corticosteroids is associated with considerable morbidity, including cardiovascular and metabolic adverse effects. Methods. This study evaluated the long-term efficacy and safety of two steroid-free regimens compared with a triple immunosuppressive therapy in renal transplant recipients. This was a 3-year follow-up to a 6-month, open-label, randomized, multicenter study. Results. Data from 3 years were available for 421 (93.3%) of 451 patients in the original intent-to-treat population (143 tacrolimus/basiliximab [Tac/Bas], 139 tacrolimus/mycophenolate mofetil [Tac/MMF], and 139 tacrolimus/MMF/steroids [triple therapy]). In the time interval from 6 months to 3 years after transplantation, the incidence of biopsy-proven acute rejection was low and similar (Tac/Bas, 2.1%; Tac/MMF, 2.2%; triple therapy, 2.2%); Most rejection episodes occurred during the first 6 months of the study. Graft survival was high (Kaplan-Meier estimates: 92.7%, 92.5%, and 92.5%), as was patient survival (93.1%, 96.4%, and 97.0%). There were 10 graft losses (n=2, 4, and 4) and 12 patient deaths (n=5, 2, and 5). Renal function was well preserved throughout the study and similar between groups. There was a trend toward improved cardiovascular risk factors in the Tac/Bas group, including reduced total and low-density lipoprotein cholesterol and lower new-onset insulin use. There were no between-group differences in the incidence or type of adverse events. Conclusion. Higher rates of acute rejection early in treatment were seen with the steroid-free regimens, but this did not translate into poorer long-term outcomes, such as graft and patient survival and renal function. A trend for a more favorable cardiovascular risk profile was observed for steroid-free immunosuppression with Tac/Bas.

  • 54.
    Krook, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Wennberg, Lars
    Hagberg, Anette
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    Song, Zhenshung
    Groth, Carl-Gustav
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Immunosuppressive drugs in islet xenotransplantation: A tool for gaining further insights in the mechanisms of the rejection process2002In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 74, no 8, p. 1084-1089Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    The aim of the present study was to examine the effect of tacrolimus (TAC) and prednisolone (PRE) in islet xenotransplantation and to use the immunosuppressive effects of these drugs and others to further characterize the mechanisms behind islet xenograft rejection.

    METHODS:

    Fetal porcine islet-like cell clusters (ICCs) were transplanted under the kidney capsule in Lewis rats. The animals were treated with TAC, cyclosporine A (CsA) plus 15-deoxyspergualin (DSG), CsA plus sirolimus (SIR) or CsA plus leflunomide (LEF), with or without the addition of PRE. Rejection was assessed by immunohistological evaluation 12 days after transplantation. In selected groups, the intragraft cytokine mRNA expression was analyzed with real-time quantitative reverse-transcriptase polymerase chain reaction (RT-PCR).

    RESULTS:

    In untreated rats, the ICC xenografts were completely rejected. Treatment with PRE alone had no, or only a marginal, protective effect. TAC alone at a dose of 1 or 0.5 mg/kg of body weight (BW) prevented xenograft rejection. The addition of PRE to TAC treatment had a paradoxical unfavorable effect. In contrast, when PRE was added to CsA-based protocols (CsA+DSG, CsA+SIR, or CsA+LEF), the immunosuppressive effect was slightly enhanced. In comparison with untreated rats, the messengers for interleukin (IL)-1beta, IL-2, IL-4, IL-10, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha were reduced in both CsA and TAC treated rats. Notably, the amount of IL-12p40 transcripts was only inhibited in rats given TAC alone, whereas this messenger was increased to approximately the same levels in untreated, CsA treated, and TAC plus PRE treated rats.

    CONCLUSIONS:

    TAC exerted a pronounced immunosuppressive effect in the pig-to-rat islet xenotransplantation model. So far, no other single drug protocol has shown a comparable efficacy. Notably, the graft protective effect of TAC was markedly abrogated when PRE was added to the treatment protocol, suggesting that TAC exerts its effect by a unique mechanism of action. In contrast with the other studied immunosuppressive regimens, treatment with TAC alone inhibited intragraft mRNA expression of all the Th1 associated cytokines, indicating that Th1 response is one important rejection mechanism that needs to be inhibited to achieve islet xenograft survival.

  • 55. Kumlien, Gunilla
    et al.
    Wilpert, Jochen
    Säfwenberg, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Tydén, Gunnar
    Comparing the tube and gel techniques for ABO antibody titration, as performed in three European centers2007In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 84, no 12, p. S17-S19Article in journal (Refereed)
    Abstract [en]

    Data from 60 consecutive ABO-incompatible kidney transplantations performed in Stockholm, Sweden; Freiburg, Germany; and Uppsala, Sweden, revealed significant variation in preoperative A/B antibody levels, with median titers of 1:32, 1:128, and 1:8, respectively. We wanted to investigate whether these differences were method-related. The same samples from 21 healthy blood donors were analyzed in the three centers using current local methods. Results confirmed method-related differences, with higher A/B titers in Freiburg and lower titers in Uppsala compared with Stockholm. Results for the same sample differed by a median of three (range 0 to 6) titer steps. When the same number of samples were analyzed in the three centers using the same gel method and the same test erythrocytes, results differed by a median of one titer step (range 0 to 4) for the same sample. In conclusion, gel hemagglutination technique significantly decreases intercenter variation compared with tube technique.

  • 56.
    Lau, Joey
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Low revascularization of human islets when experimentally transplanted into the liver2009In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 87, no 3, p. 322-325Article in journal (Refereed)
    Abstract [en]

    Previously, we have found that human islets experimentally transplanted beneath the kidney capsule have lower vascular density than native islets. This study aimed to investigate whether human islets experimentally transplanted into the liver are also poorly revascularized in the same manner as islets at the renal subcapsular site. Human islets were transplanted to nude mice. One month posttransplantation, the islet graft-bearing livers or kidneys were removed, formalin-fixed, and stained with the lectin Bandeiraea (Griffonia) simplicifolia (BS-1) to visualize endothelium. The vascular density in the intraportally transplanted human islets was found to be similarly low as in human islets transplanted beneath the kidney capsule. The intrahepatic human islets were coated with numerous vessels, but few vessels could be seen within the islets. Human islets transplanted intraportally into the liver become poorly revascularized. This could contribute to the loss of function in human islets transplanted into the liver over time.

  • 57.
    Lau, Joey
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Vasylovska, Svitlana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kozlova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Surface-Coating of Pancreatic Islets with Neural Crest Stem Cells Improves Islet Engraftment and Function After Intraportal Transplantation2013In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 96, no 6, p. S111-S111Article in journal (Other academic)
  • 58.
    Lilja, Helene
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Paediatric Surgery.
    Arkadopoulos, N
    Blanc, P
    Eguchi, S
    Middleton, Y
    Meurling, S
    Demetriou, A A
    Rozga, J
    Fetal rat hepatocytes: Isolation, characterization and transplantation in the Nagase analbuminemic rats1997In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 64, no 9, p. 1240-1248Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    In contrast to adult hepatocytes, fetal hepatocytes (FH) are thought to be highly proliferative, less immunogenic, and resistant to cryopreservation and ischemic injury. These qualities could enhance FH engraftment, proliferation, and gene transfer requiring active DNA synthesis.

    METHODS:

    Rat FH were obtained using the nonperfusion collagenase/DNase digestion method. Free and cultured cells were studied using electron microscopy, fluorescence-activated cell sorting, and Northern analysis using alpha-fetoprotein and albumin as markers of hepatocyte lineage. DNA synthetic activity was measured in quiescent and mitogen-stimulated fetal and adult hepatocytes by [3H]thymidine incorporation. Susceptibility of cultured FH to retrovirally mediated gene transfer was studied using an amphotropic retroviral vector carrying the Escherichia coli lac-Z gene. Nagase analbuminemic rats were used as recipients to study the effects of intraportal FH transplantation. Analysis of serum albumin was carried out by enzyme-linked immunosorbent assay.

    RESULTS:

    In fetal liver, 87+/-2% of the cells showed morphological and molecular features of hepatocytes. DNA synthetic activity in nonstimulated cultured FH was 10 times greater than the maximal hepatocyte growth factor-driven response in adult rat hepatocytes. A total of 5-15% FH stained positive for X-gal; results of transduction in adult hepatocyte cultures were negative. In Nagase analbuminemic rat recipients, FH produced significant amounts of albumin only when a hepatic regenerative stimulus was applied. Immunohistochemistry confirmed presence of albumin-positive hepatocytes.

    CONCLUSIONS:

    Fetal rat liver from the late gestation period is highly enriched with hepatocyte progenitors. They are highly proliferative and susceptible to retroviral transduction and can engraft and function in the adult rat liver if transplanted under a hepatic regenerative stimulus.

  • 59.
    Lilja, Helene
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Arkadopoulos, N
    Blanc, P
    Eguchi, S
    Middleton, Yvette
    Meurling, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Demetriou, A A
    Rozga, J
    Fetal rat hepatocytes: Isolation, characterization and transplantation in the Nagase analbuminernic rats1997In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 64, no 9, p. 1240-1248Article in journal (Refereed)
    Abstract [en]

    Background. In contrast to adult hepatocytes, fetal hepatocytes (FH) are thought to be highly proliferative, less immunogenic, and resistant to cryopreservation and ischemic injury. These qualities could enhance FH engraftment, proliferation, and gene transfer requiring active DNA synthesis,

    Methods. Rat FH were obtained using the nonperfusion collagenase/DNase digestion method, Free and cultured cells were studied using electron microscopy, fluorescence-activated cell sorting, and Northern analysis using alpha-fetoprotein and albumin as markers of hepatocyte lineage, DNA synthetic activity was measured in quiescent and mitogen-stimulated fetal and adult hepatocytes by [H-3]thymidine incorporation, Susceptibility of cultured FH to retrovirally mediated gene transfer was studied using an amphotropic retroviral vector carrying the Escherichia coli lac-Z gene, Nagase analbuminemic rats were used as recipients to study the effects of intraportal FH transplantation, Analysis of serum albumin was carried out by enzyme-linked immunosorbent assay.

    Results, In fetal liver, 87+/-2%? of the cells showed morphological and molecular features of hepatocytes. DNA synthetic activity in nonstimulated cultured FH was 10 times greater than the maximal hepatocyte growth factor-driven response in adult rat hepatocytes., A total of 5-15% FH stained positive for X-gal; results of transduction in adult hepatocyte cultures were negative. In Nagase analbuminemic rat recipients, FH produced significant amounts of albumin only when a hepatic regenerative stimulus was applied. Immunohistochemistry confirmed presence of albumin-positive hepatocytes,

    Conclusions, Fetal rat liver from the late gestation period is highly enriched with hepatocyte progenitors, They are highly proliferative and susceptible to retroviral transduction and can engraft and function in the adult rat liver if transplanted under a hepatic regenerative stimulus.

  • 60.
    Liljebäck, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Olerud, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Engraftment Factors Limiting Human Islet Survival and Function After Experimental Intraportal Islet Transplantation2013In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 96, no 6, p. S130-S130Article in journal (Other academic)
  • 61.
    Linde, Torbjörn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ekberg, Henrik
    Forslund, Terje
    Furuland, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Holdaas, Hallvard
    Nyberg, Gudrun
    Tydén, Gynnar
    Wahlberg, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Danielson, Bo G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    The use of pretransplant erythropoietin to normalize hemoglobin levels has no deleterious effects on renal transplantation outcome2001In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 71, no 1, p. 79-82Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The aim of this study was to establish the outcome of renal transplantation in patients given pretransplant erythropoietin (EPO) treatment targeted at reaching a normal hemoglobin concentration (Hb), compared to those given EPO-treatment aimed at maintaining subnormal Hb.

    METHODS: A total of 416 patients from Scandinavian countries and with renal anaemia were enrolled to examine the effects of increasing Hb from a subnormal level (90-120 g/liter) to a normal level (135-160 g/liter) by EPO treatment. Half of the patients were randomized to have their Hb increased, with the other half randomized to maintain a subnormal Hb. Thirty-two patients from the normal Hb group and 24 patients from the subnormal group received a renal graft during the study period. The outcomes of these transplantations were examined prospectively for 6 months.

    RESULTS: Preoperative Hb levels were 143+/-17 and 121+/-14 g/liter in the two groups, respectively (P<0.0001). The Hb remained higher in the normal Hb group during the first 2 weeks after transplantation. The percentage of patients requiring postoperative blood transfusions in the normal Hb group was 16%, compared with 50% in the subnormal group (P<0.01). No statistically significant difference in the proportion of functioning grafts or in the serum creatinine levels could be detected. No correlation between EPO treatment and creatinine levels after transplantation was found. The frequency of adverse events was similar in the two groups.

    CONCLUSIONS: EPO treatment aimed at reaching a normal Hb in renal transplant recipients reduces the postoperative requirement for blood transfusions and has no deleterious effects on kidney graft function.

  • 62.
    Markmann, James F.
    et al.
    Massachusetts Gen Hosp, Div Transplantat, Boston, MA 02114 USA..
    Bartlett, Stephen T.
    Univ Maryland, Sch Med, Dept Surg, Baltimore, MD 21201 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 Inst Med Res, 41 Victoria Parade, Fitzroy, Vic 3065, Australia.;Univ Melbourne, St Vincents Hosp, Dept Med, Melbourne, Vic 3010, Australia..
    Bromberg, Jonathan
    Univ Maryland, Sch Med, Dept Surg, Baltimore, MD 21201 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, Philip J.
    Univ Sydney, Westmead Hosp, Ctr Transplant & Renal Res, Westmead Millennium Inst, Westmead, NSW 2145, Australia..
    Stabler, Cherie
    Univ Florida, Dept Biomed Engn, Gainesville, FL USA..
    Matsumoto, Shinichi
    Otsuka Pharmaceut Factory Inc, Naruto, Japan.;Natl Ctr Global Hlth & Med, Tokyo, Japan..
    Ludwig, Barbara
    Tech Univ Dresden, Dept Med 3, D-01062 Dresden, Germany.;Tech Univ Dresden, Univ Clin Carl Gustav Carus, Helmholtz Ctr Munich, 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..
    Khovatchev, 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
    Columbia 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, Melbourne, Vic, Australia.;Monash Univ, Melbourne, Vic 3004, Australia..
    Ricordi, Camillo
    Univ Miami, 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..
    Executive Summary of IPITA-TTS Opinion Leaders Report on the Future of beta-Cell Replacement2016In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 100, no 7, p. E25-E31Article, review/survey (Refereed)
    Abstract [en]

    The International Pancreas and Islet Transplant Association (IPITA), in conjunction with the Transplantation Society (TTS), convened a workshop to consider the future of pancreas and islet transplantation in the context of potential competing technologies that are under development, including the artificial pancreas, transplantation tolerance, xenotransplantation, encapsulation, stem cell derived beta cells, beta cell proliferation, and endogenous regeneration. Separate workgroups for each topic and then the collective group reviewed the state of the art, hurdles to application, and proposed research agenda for each therapy that would allow widespread application. Herein we present the executive summary of this workshop that focuses on obstacles to application and the research agenda to overcome them; the full length article with detailed background for each topic is published as an online supplement to Transplantation.

  • 63.
    Ogasawara, Hiroyuki
    et al.
    Tohoku Univ, Grad Sch Med, Dept Surg, Sendai, Miyagi, 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, Tokyo, Japan.
    Imura, Takehiro
    Tohoku Univ, Div Transplantat & Regenerat Med, Sendai, Miyagi, Japan.
    Inagaki, Akiko
    Tohoku Univ, Div Transplantat & Regenerat Med, Sendai, Miyagi, Japan.
    Saito, Yoshikatsu
    Tohoku Univ, Grad Sch Med, Dept Surg, Sendai, Miyagi, Japan.
    Matsumura, Muneyuki
    Tohoku Univ, Grad Sch Med, Dept Surg, Sendai, Miyagi, Japan.
    Fukuoka, Kengo
    Tohoku Univ, Grad Sch Med, Dept Surg, Sendai, Miyagi, Japan.
    Fathi, Ibrahim
    Tohoku Univ, Div Transplantat & Regenerat Med, Sendai, Miyagi, Japan.
    Miyagi, Shigehito
    Tohoku Univ, Grad Sch Med, Dept Surg, Sendai, Miyagi, Japan.
    Nilsson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ohashi, Kazuo
    Osaka Univ, Grad Sch Pharmaceut Sci, Osaka, Japan.
    Unno, Michiaki
    Tohoku Univ, Grad Sch Med, Dept Surg, Sendai, Miyagi, Japan.
    Kamei, Takashi
    Tohoku Univ, Grad Sch Med, Dept Surg, Sendai, Miyagi, Japan.
    Satomi, Susumu
    Tohoku Univ, Grad Sch Med, Dept Surg, Sendai, Miyagi, Japan.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Gustafson, Elisabet K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Pediatric Surgery.
    Goto, Masafumi
    Tohoku Univ, Grad Sch Med, Dept Surg, Sendai, Miyagi, Japan;Tohoku Univ, Div Transplantat & Regenerat Med, Sendai, Miyagi, Japan.
    The Optimization of the Hepatocyte Surface Modification Procedures in Terms of Heparin and Apyrase for Improving Hepatocyte Engraftment2018In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 102, p. S727-S727Article in journal (Other academic)
  • 64.
    Olsson, Richard F.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Karolinska Univ Hosp, Ctr Allogene Stem Cell Transplantat, Huddinge, Sweden.;Karolinska Inst, Dept Lab Med, Div Therapeut Immunol, SE-14186 Stockholm, Sweden..
    Hagelberg, Stefan
    Karolinska Univ Hosp, Dept Paediat, Stockholm, Sweden..
    Schiller, Bodil
    Sachs Childrens & Youth Hosp, Dept Clin Sci & Educ, Karolinska Inst, Sodersjukhuset, Stockholm, Sweden..
    Ringden, Olle
    Karolinska Univ Hosp, Ctr Allogene Stem Cell Transplantat, Huddinge, Sweden.;Karolinska Inst, Dept Lab Med, Div Therapeut Immunol, SE-14186 Stockholm, Sweden..
    Truedsson, Lennart
    Lund Univ, Dept Lab Med, Sect Microbiol Immunol & Glycobiol, Lund, Sweden..
    Ahlin, Anders
    Sachs Childrens & Youth Hosp, Dept Clin Sci & Educ, Karolinska Inst, Sodersjukhuset, Stockholm, Sweden..
    Allogeneic Hematopoietic Stem Cell Transplantation in the Treatment of Human C1q Deficiency: The Karolinska Experience2016In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 100, no 6, p. 1356-1362Article in journal (Refereed)
    Abstract [en]

    Background. Human C1q deficiency is associated with systemic lupus erythematosus (SLE) and increased susceptibility to severe bacterial infections. These patients require extensive medical therapy and some develop treatment-resistant disease. Because C1q is produced by monocytes, it has been speculated that allogeneic hematopoietic stem cell transplantation (allo-HSCT) may cure this disorder. Methods. We have so far treated 5 patients with C1q deficiency. In 3 cases, SLE symptoms remained relatively mild after the start of medical therapy, but 2 patients developed treatment-resistant SLE, and we decided to pursue treatment with allo-HSCT. For this purpose, we chose a conditioning regimen composed of treosulfan (14 g/m(2)) and fludarabine (30 mg/m(2)) started on day -6 and given for 3 and 5 consecutive days, respectively. Thymoglobulin was given at a cumulative dose of 8 mg/ kg, and graft-versus-host disease prophylaxis was composed of cyclosporine and methotrexate. Results. A 9-year-old boy and a 12-year-old girl with refractory SLE restored C1q production after allo-HSCT. This resulted in normal functional properties of the classical complement pathway followed by reduced severity of SLE symptoms. The boy developed posttransplant lymphoproliferative disease, which resolved after treatment with rituximab and donor lymphocyte infusion. Unfortunately, donor lymphocyte infusion induced severe cortisone-resistant gastrointestinal graft-versus-host disease, and the patient died from multiple organ failure 4 months after transplantation. The girl is doing well 33 months after transplantation, and clinically, all signs of SLE have resolved. Conclusions. Allo-HSCT can cure SLE in human C1q deficiency and should be considered early in subjects resistant to medical therapy.

  • 65.
    Olsson, Richard
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Maxhuni, Arber
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Revascularization of transplanted pancreatic islets following culture with stimulators of angiogenesis2006In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 82, no 3, p. 340-347Article in journal (Refereed)
    Abstract [en]

    Background. Insufficient revascularization of transplanted islets may result in chronic hypoxia and loss of islet function. This study investigated whether simple culture of islets with angiogenic substances before transplantation could improve graft revascularization.

    Methods. Mouse islets were cultured with vascular endothelial growth factor (VEGF; 20 ng/ml), fibroblast growth factor 2 (FGF-2; 20 ng/ml) or matrix metalloproteinase 9 (MMP-9; 1 mu g/ml). Thereafter, 250 islets were implanted beneath the renal capsule of syngeneic C57Bl/6 mice. One month posttransplantation, blood flow (laser-Doppler flowmetry), oxygen tension (Clark microelectrodes), and vascular density were measured and correlated to graft function.

    Results. Treatment of islets with VEGF during culture caused islet blood vessels to dilate, whereas FGF-2 treatment induced endothelial cell proliferation. However, the number of capillaries in both cases decreased during culture. When investigated one month posttransplantation, both VEGF and FGF-2 pretreated islets had similar or worse vascular engraftment when compared to transplanted control islets. MMP-9 pretreatment of islets increased vascular density, blood flow and oxygen tension within the grafts. Animals receiving MMP-9 pretreated islets returned, however, more slowly to normoglycemia than control animals, and performed worse than controls in a glucose tolerance test one month posttransplantation.

    Conclusions. Treatment of islets during culture with VEGF or FGF-2 changed the islet vascular phenotype, but capillaries were still lost. Notably, the number of capillaries in the grafted islets one month posttransplantation was in all cases strikingly similar to that observed prior to transplantation. MMP-9 pretreatment of islets elicited an angiogenic response, which improved revascularization of the transplanted islets.

  • 66.
    Penno, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Johnsson, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Ultrasmall iron oxide particle contrast agent and MRI can be used to monitor the effect of anti-rejection treatment2007In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 84, no 3, p. 374-379Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The purpose of the study was to investigate the feasibility of monitoring anti-rejection treatment using a blood pool contrast agent and magnetic resonance (MR) imaging. METHODS: Allogeneic heterotopic heart transplantations in rats were performed. In one group (treated group), a mild acute rejection was developed and subsequently treated and MR imaging was performed before and after anti-rejection treatment. In the other group (nontreated group), a mild acute rejection was developed and allowed to progress without treatment and MR examinations were performed before and after the advance of the acute rejection. After injecting ultrasmall superparamagnetic contrast agent, the relative change of signal intensity (SI) over time was measured. The SI difference between both radiological investigations for every animal was calculated; hence, every animal served as its own control. RESULTS: In both treated and nontreated groups, a significant difference over time was found between the two MR examinations seen as a decrease in the treated group and an increase in the nontreatment group. CONCLUSION: It is concluded that the effect of anti-rejection treatment can be detected using a blood pool agent and MR imaging, as a change in SI corresponding to changes in the vascular permeability.

  • 67. Pihlstrom, H.
    et al.
    Dahle, D.
    Mjoen, G.
    Pilz, S.
    Maerz, W.
    Holme, I.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Jardine, A.
    Holdaas, H.
    Hyperparathyroidism in Stable Renal Transplant Recipients Is Associated With All-Cause Mortality and Renal Graft Loss2014In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 98, p. 126-126Article in journal (Other academic)
  • 68. Pihlstrom, H.
    et al.
    Mjoen, G.
    Dahle, D.
    Pilz, S.
    Midtvedt, K.
    Maerz, W.
    Abedini, S.
    Holme, I.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Holdaas, H.
    Symmetric Dimethylarginine as Predictor of Graft Loss and All-Cause Mortality in Renal Transplant Recipients2014In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 98, p. 102-102Article in journal (Other academic)
  • 69. Pihlstrom, Hege
    et al.
    Dahle, Dag Olav
    Mjoen, Geir
    Pilz, Stefan
    Maerz, Winfried
    Abedini, Sadollah
    Holme, Ingar
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Jardine, Alan G.
    Holdaas, Hallvard
    Increased Risk of All-Cause Mortality and Renal Graft Loss in Stable Renal Transplant Recipients With Hyperparathyroidism2015In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 99, no 2, p. 351-359Article in journal (Refereed)
    Abstract [en]

    Background. Hyperparathyroidism is reported in 10% to 66% of renal transplant recipients (RTR). The influence of persisting hyperparathyroidism on long-term clinical outcomes in RTR has not been examined in a large prospective study. Methods. We investigated the association between baseline parathyroid hormone (PTH) levels and major cardiovascular events, renal graft loss, and all-cause mortality by Cox Proportional Hazard survival analyses in 1840 stable RTR derived from the Assessment of LEscol in Renal Transplantation trial. Patients were recruited in a mean of 5.1 years after transplantation, and follow-up time was 6 to 7 years. Results. Significant associations between PTH and all 3 outcomes were found in univariate analyses. When adjusting for a range of plausible confounders, including measures of renal function and serum mineral levels, PTH remained significantly associated with all-cause mortality (4% increased risk per 10 units; P = 0.004), and with graft loss (6% increased risk per 10 units; P < 0.001), but not with major cardiovascular events. Parathyroid hormone above the upper limit of normal (65 pg/mL) indicated a 46% (P = 0.006) higher risk of death and an 85% higher risk of graft loss (P < 0.001) compared with low/normal values. Conclusions. Hyperparathyroidismis an independent, potentially remediable, risk factor for renal graft loss and all-cause mortality in RTR.

  • 70. Pihlstrom, Hege
    et al.
    Mjoen, Geir
    Dahle, Dag Olav
    Pilz, Stefan
    Midtvedt, Karsten
    Marz, Winfried
    Abedini, Sadollah
    Holme, Ingar
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Jardine, Alan
    Holdaas, Hallvard
    Symmetric Dimethylarginine as Predictor of Graft loss and All-Cause Mortality in Renal Transplant Recipients2014In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 98, no 11, p. 1219-1225Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Elevated symmetric dimethylarginine (SDMA) has been shown to predict cardiovascular events and all cause mortality in diverse populations. The potential role of SDMA as a risk marker in renal transplant recipients (RTR) has not been investigated. METHODS: We analyzed SDMA in the placebo arm of the Assessment of Lescol in Renal Transplantation study, a randomized controlled trial of fluvastatin in RTR. Mean follow-up was 5.1 years. Patients were grouped into quartiles based on SDMA levels at study inclusion. Relationships between SDMA and traditional risk factors for graft function and all-cause mortality were analyzed in 925 RTR using univariate and multivariate survival analyses. RESULTS: In univariate analysis, SDMA was significantly associated with renal graft loss, all-cause death, and major cardiovascular events. After adjustment for established risk factors including estimated glomerular filtration rate, an elevated SDMA-level (4th quartile, >1.38 mumol/L) was associated with renal graft loss; hazard ratio (HR), 5.51; 95% confidence interval (CI), 1.95-15.57; P=0.001, compared to the 1st quartile. Similarly, SDMA in the 4th quartile was independently associated with all-cause mortality (HR, 4.56; 95% CI, 2.15-9.71; P<0.001), and there was a strong borderline significant trend for an association with cardiovascular mortality (HR, 2.86; 95% CI, 0.99-8.21; P=0.051). CONCLUSION: In stable RTR, an elevated SDMA level is independently associated with increased risk of all-cause mortality and renal graft loss.

  • 71.
    Ringden, Olle
    et al.
    Karolinska Inst, Karolinska Univ Hosp, Translat Cell Therapy Res, Stockholm, Sweden;Karolinska Inst, Karolinska Univ Hosp, Dept Clin Sci Intervent & Technol, Stockholm, Sweden.
    Remberger, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Karolinska Inst, Karolinska Univ Hosp, Dept Oncol & Pathol, Stockholm, Sweden;Uppsala Univ, Dept Med Sci, Uppsala, Sweden;Uppsala Univ Hosp, KFUE, Uppsala, Sweden.
    Gustafsson, Britt
    Karolinska Inst, Karolinska Univ Hosp, Dept Clin Sci Intervent & Technol, Stockholm, Sweden;Karolinska Inst, Karolinska Univ Hosp, Dept Pediat, Stockholm, Sweden.
    Moretti, Gianluca
    Karolinska Inst, Karolinska Univ Hosp, Translat Cell Therapy Res, Stockholm, Sweden;Karolinska Inst, Karolinska Univ Hosp, Dept Clin Sci Intervent & Technol, Stockholm, Sweden.
    Mattsson, Jonas
    Karolinska Inst, Karolinska Univ Hosp, Dept Oncol & Pathol, Stockholm, Sweden;Karolinska Inst, Karolinska Univ Hosp, Dept Pediat, Stockholm, Sweden;Karolinska Inst, Karolinska Univ Hosp, Dept Clin Immunol, Stockholm, Sweden.
    Winiarski, Jacek
    Karolinska Inst, Karolinska Univ Hosp, Dept Clin Sci Intervent & Technol, Stockholm, Sweden.
    Sadeghi, Behnam
    Karolinska Inst, Karolinska Univ Hosp, Translat Cell Therapy Res, Stockholm, Sweden;Karolinska Inst, Karolinska Univ Hosp, Dept Clin Sci Intervent & Technol, Stockholm, Sweden.
    The Outcome of Allogeneic Hematopoietic Stem Cell Transplantation for Inherited Diseases Is Influenced by HLA Match, Year of Transplantation, and Immunized Female Donor2019In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 103, no 6, p. 1247-1252Article in journal (Refereed)
    Abstract [en]

    Background. For many inborn errors of metabolism (IEM), allogeneic hematopoietic stem cell transplantation (HSCT) is the only cure. Methods. We report the outcome in 160 patients with inherited diseases, who were treated with HSCT in 3 decades. Median age was 3 years (range 0.1-63). Grafts were from matched related donors (MRDs, 56), matched unrelated donors (MUDs, 66), or HLA-mismatched donors (38). Results. Graft failure (GF) occurred in 26 patients (16%), severe acute graft-versus-host disease (GVHD) in 9 (6%), and chronic GVHD in 23 (12%). Ten-year survival was 64% before the year 2000 and 86% after that (P = 0.01). Ten-year survival for MRD grafts was 90%, as opposed to 79% for MUD grafts and 56% for HLA-mismatched grafts (P = 0.03). In multivariate analysis, GF was associated with having an HLA-mismatched donor (P < 0.05) or MUD (P = 0.015) and with reduced-intensity conditioning (P < 0.01). Death was associated with year of transplant (P = 0.015), having an HLA-mismatched donor (P < 0.001), and being a male recipient from an immune female donor (P = 0.05). Conclusions. The outcome after HSCT for IEM depends on HLA match, year and immune female donor.

  • 72. Ringdén, Olle
    et al.
    Söderdahl, Gunnar
    Mattson, Jonas
    Uzunel, Mehmet
    Remberger, Mats
    Hentschke, Patrik
    Hägglund, Hans
    Sparrelid, Elda
    Elmhorn-Rosenborg, Annika
    Duraj, Frans
    Department of Transplantation Surgery, Karolinska Institute, Stockholm, Sweden.
    Zetterquist, Henrik
    Ericzon, Bo-Göran
    Transplantation of Autologous and Allogeneic Bone Marrow With Liver From A Cadaveric Donor for Primary Liver Cancer12000In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 69, no 10, p. 2043-2048Article in journal (Other academic)
    Abstract [en]

    Background

    In histocompatibility mismatched experimental animals, a combination of T-cell-depleted autologous and allogeneic marrow may induce mixed chimerism and tolerance. Patients with large primary liver tumors have a poor outcome. We investigated whether it were possible to induce mixed chimerism and obtain an antitumor effect in a patient with a large primary liver cancer after combined liver and bone marrow transplantation (BMT).

    Methods

    A 46-year-old female with a primary non resectable liver cancer received a liver transplant from a cadaveric donor. Subsequently, she was conditioned with 4×2 Gy of total lymphoid irradiation, 120 mg/kg cyclophosphamide, and 7.5 Gy total body irradiation. Twelve days after liver transplantation, she received T-cell-depleted autologous : cadaveric 5/6 antigen HLA-mismatched marrow in a proportion of CD34+ cells of 0.5 : 3.0×106/kg. Chimerism status was determined with polymerase chain reaction amplification of variable number tandem repeats from DNA obtained from CD3+, CD19+, and CD45+ magnetic-bead-separated cells.

    Results

    The early posttransplant period was uneventful; liver function was normal and the hematopoietic engraftment of donor and recipient origin was prompt. [alpha]-fetoprotein levels dropped from 440 to 35 µg/l. One month after marrow transplantation, donor T-cells decreased markedly. Monoclonal antibody OKT-3 and 105/kg donor T-cells were given. One month later, the patient developed diarrhea and abdominal pain. A colonoscopy showed moderate gastrointestinal acute graft-versus-host disease and a Cryptosporidium infection. Three months after BMT, she became a complete donor chimera. Chimera cells showed little, if any, reactivity in mixed lymphocyte cultures to recipient and donor cells, but reacted to third party. Five months after BMT, she developed progressive Aspergillus fumigatus pneumonia and died. No tumor was found at the autopsy.

    Conclusion

    We obtained mixed donor-recipient hematopoietic chimerism without severe acute graft-versus-host-disease, after combined T-cell depleted autologous and allogeneic BMT and a transplantation of a liver from an HLA-mismatched cadaveric donor. Additional donor T-cells enhanced donor bone marrow engraftment, but rejected the autograft. On the basis of this first attempt, further clinical studies are warranted.

  • 73.
    Rodriguez, Andres
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Audolfsson, Thorir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Wong, Corrine
    Univ Texas SW Med Ctr Dallas, Plast Surg, Dallas, TX 75390 USA..
    Cheng, Angela
    Univ Texas SW Med Ctr Dallas, Plast Surg, Dallas, TX 75390 USA..
    Nowinski, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Rozen, Shai
    Univ Texas SW Med Ctr Dallas, Plast Surg, Dallas, TX 75390 USA..
    Influence of Using a Single Facial Vein as Outflow in Full Face Transplantation: A Three-Dimensional Computed Tomographic Study2015In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 99, p. S25-S25Article in journal (Other academic)
  • 74.
    Rodriguez, Andres
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Audolfsson, Thorir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Wong, Corrine
    Univ Texas SW Med Ctr Dallas, Plast Surg, Dallas, TX 75390 USA..
    Cheng, Angela
    Univ Texas SW Med Ctr Dallas, Plast Surg, Dallas, TX 75390 USA..
    Nowinski, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Rozen, Shai
    Univ Texas SW Med Ctr Dallas, Plast Surg, Dallas, TX 75390 USA..
    Nerve Transfers in Face Transplantation2015In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 99, p. S26-S26Article in journal (Other academic)
  • 75. Sahraoui, Afaf
    et al.
    Hoeyem, Merete
    Winzell, Maria Soerhede
    Smith, Dave
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Foss, Aksel
    Scholz, Hanne
    Expanding the Donor Pool in Islet Transplantation: Age Impacts Parameters Regulating Glucose Metabolism2013In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 96, no 6, p. S66-S66Article in journal (Other academic)
  • 76.
    Sandberg, Monica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Fredrik
    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.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Syngeneic islet transplantation into the submandibular gland of mice2011In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 91, no 2, p. e17-e19Article in journal (Refereed)
  • 77.
    Sandberg, Monica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Fredrik
    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.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Syngeneic islet transplantations into the submandibular gland of mice2011In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 91, no 2, p. e17-e19Article in journal (Other academic)
  • 78.
    Sandberg, Monica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lau, Joey
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Draft Copy Incorporation of Gelatin Scaffolds with Islets for Transplantation Improves Islet Engraftment and Post Transplant Function2013In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 96, no 6, p. S127-S127Article in journal (Other academic)
  • 79.
    Schmidt, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Goto, Masafumi
    Le Mauff, Brigitte
    Anegon, Ignacio
    Korsgren, Olle
    Adenovirus-mediated expression of human CD55 or CD59 protects adult porcine islets from complement-mediated cell lysis by human serum2003In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 75, no 5, p. 697-702Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Protection against complement activation may reduce acute islet damage in pig-to-human islet xenotransplantation. Expression of the human complement regulatory proteins decay-accelerating factor (DAF, CD55) or CD59 was induced on intact adult porcine islets (APIs) by adenoviral transduction. The functional capacity of the transgenes was examined in vitro after exposure to fresh human serum.

    METHODS: Intact APIs were transduced with adenoviral vectors Ad.hDAF or Ad.hCD59 or a control vector. After 3 days, the islets were trypsin dissociated to a single-cell suspension. A cytotoxicity assay was performed in which the islet cells were incubated with human complement active AB serum. Flow cytometry and immunohistochemistry were used to evaluate transgene expression.

    RESULTS: APIs could be transduced to express hDAF or hCD59. Flow cytometry analysis of islet single cells revealed that only a fraction of the cells expressed the transgene; immunohistochemical staining of transduced islets demonstrated that mainly cells located in the periphery of the islets were expressing the protein. Cells from nontransduced islets or islets expressing the control protein were sensitive to lysis in human sera (66+/-4.0% and 73+/-3.7% cytotoxicity, respectively). Single cells from islets transduced with hDAF and hCD59 were partially protected from lysis. Islet cells expressing hCD59 were slightly less sensitive to lysis (33+/-3.3%) than cells expressing hDAF (45+/-3.5%).

    CONCLUSIONS: These data show that intact pig islets can be transduced to express human regulators of complement activation on the surface and that pig islet cells expressing hDAF or hCD59 are less sensitive to complement-mediated lysis.

  • 80. Schmidt, Peter
    et al.
    Magnusson, Caroline
    Lundgren, Torbjörn
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Low molecular weight dextran sulfate is well tolerated in humans and increases endogenous expression of islet protective hepatocyte growth factor2008In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 86, no 11, p. 1523-1530Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Low molecular weight dextran sulfate (LMW-DS) is a strong candidate to prevent early islet graft destruction caused by the instant blood-mediated inflammatory reaction. Pharmacokinetics, safety, tolerability, and the effect on endogenous release of various growth factors were studied in humans. MATERIALS AND METHODS: Thirty healthy volunteers were given LMW-DS as a combined bolus and 20 min intravenous infusion followed by a continuous intravenous infusion for 5 hr to reach different predetermined target-activated partial thromboplastin times (APTT) in five study groups. Monitoring of APTT was used to estimate and control the plasma concentration. Safety, including hemostasis parameters, was evaluated before proceeding to a higher target APTT-level. Plasma was collected continuously during the infusion and was analyzed for additional safety markers and the presence of six different growth factors. RESULTS: Predetermined target APTT levels were reached and kept for 5 hr without extensive dose corrections. After the 5 hr 20 min of LMW-DS infusion, the subjects in the highest dose group (target APTT=150 s) were back at APTT-levels below 75 s within 60 min. Plasma levels of hepatocyte growth factor were increased 100-fold within 20 min of infusion start and persisted more than 8 hr in the two highest dose groups. CONCLUSION: At doses that maintain APTT at up to 150 s for 5 hrs 20 min, LMW-DS could be safely infused without affecting the platelet count or revealing other signs of increased bleeding risk. The observed endogenous release of islet protective hepatocyte growth factor could be an additional beneficial effect of LMW-DS during the first critical hours after transplantation.

  • 81.
    Sedigh, Amir
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Nordling, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Carlsson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Norlin, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Lubenow, Norbert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lennmyr, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Magnusson, Peetra
    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.
    Perfusion of Porcine Kidneys With Macromolecular Heparin Reduces Early Ischemia Reperfusion Injury2019In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 103, no 2, p. 420-427Article in journal (Refereed)
    Abstract [en]

    Background: Previously, we have been able to demonstrate the possibility of coating the inner surface of the renal arteries in porcine kidneys with a heparin conjugate during hypothermic machine perfusion (HMP). The purpose of this study was to assess the efficacy of this treatment in reducing early ischemia-reperfusion injury.

    Method: Brain death was induced in male landrace pigs by stepwise volume expansion of an epidural balloon catheter until negative cerebral perfusion pressure (CPP) was obtained. Both kidneys (matched pairs; n = 6 + 6) were preserved for 20 hours byHMP during which 50mg heparin conjugate was added to one of the HMP systems (treated group). A customized ex vivo normothermic oxygenated perfusion (NP) system with added exogenous creatinine was used to evaluate early kidney function. Blood, urine and histological samples were collected during the subsequent 3 hours of NP.

    Results: Kidney weight was lower at the end of NP (P = 0.017) in the treated group compared with control kidneys. The rate of decline in creatinine level was faster (P = 0.024), total urinary volume was higher (P = 0.031), and the level of urine neutrophil gelatinase-associated lipocalin (NGAL) was lower (P = 0.031) in the treated group. Histologically, less tubular changes were seen (P = 0.046). During NP intrarenal resistance remained lower (P < 0.0001) in the treated group.

    Conclusions: Perfusion of porcine kidneys with heparin conjugate during HMP reduces preservation injury and improves organ function shortly after reperfusion. No increased risk of bleeding was seen in this setup. This protective strategy may potentially improve the quality of transplanted kidneys in the clinical setting.

  • 82.
    Sjöberg, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Biglarnia, Alireza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Weis, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Assessing the Viability of Human Pancreas Grafts using 31P MR Spectroscopy - a Pilot Study2013In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 96, no 6, p. S13-S13Article in journal (Other academic)
  • 83.
    Soveri, Inga
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Holme, Ingar
    Holdaas, Hallvard
    Budde, Klemens
    Jardine, Alan G
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    A Cardiovascular Risk Calculator for Renal Transplant Recipients2012In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 94, no 1, p. 57-62Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Renal transplant recipients (RTRs) have increased cardiovascular disease (CVD) risk. Standard CVD risk calculators are poorly predictive in RTRs; we therefore aimed to develop and validate an equation for CVD risk prediction in this population.

    METHODS:

    We used data from the Assessment of Lescol in Renal Transplantation trial, which are randomly divided into an assessment sample and a test sample (67% and 33%, respectively, of the total population). For variable selection in the assessment sample, backward stepwise Cox regression was used. Using the regression coefficients and centralized prognostic index, risk was calculated for individual patients. The equation was then validated for calibration and discrimination using the test sample.

    RESULTS:

    Major adverse cardiac events could be predicted using a seven-variable model including age, previous coronary heart disease, diabetes, low-density lipoprotein, creatinine, number of transplants, and smoking. The calibration of the model was good in the test sample with a Hosmer-Lemeshow chi-square value of 11.47 and a P value of 0.245. The areas under the receiver operating characteristic curve were 0.738 in the assessment sample and 0.740 in the test sample. Total mortality could be predicted using a six-variable model including age, coronary heart disease, diabetes, creatinine, total time on renal replacement therapy, and smoking. The calibration of the model was acceptable in the test sample with a Hosmer-Lemeshow chi-square value of 13.08 and a P value of 0.109. The areas under the receiver operating characteristic curve were 0.734 in the assessment sample and 0.720 in the test sample.

    CONCLUSIONS:

    Using the Assessment of Lescol in Renal Transplantation trial population, a formula for 7-year CVD and mortality risk calculation for prevalent RTRs has been developed.

  • 84.
    Soveri, Inga
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Snyder, Jon
    Holdaas, Hallvard
    Holme, Ingar
    Jardine, Alan G.
    L'Italien, Gilbert J.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    The External Validation of the Cardiovascular Risk Equation for Renal Transplant Recipients: Applications to BENEFIT and BENEFIT-EXT Trials2013In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 95, no 1, p. 142-147Article in journal (Refereed)
    Abstract [en]

    Background. Renal transplant recipients (RTRs) have increased cardiovascular disease risk. Recently, major adverse cardiac event (MACE) and mortality risk calculators for prevalent RTRs were developed. We aimed to externally validate these risk equations in an international transplant database and subsequently demonstrate application to 2 clinical trials: Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT) and Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial-EXTended criteria donors (BENEFIT-EXT). Methods. The 7-year risk calculators were developed using data from the ALERT trial and validated for discrimination and calibration in the Patient Outcomes in Renal Transplantation (PORT) study cohort. The outlier laboratory readings were trimmed to the 99th percentile observed in the PORT database. Diabetes mellitus, LDL-cholesterol, and serum creatinine values 3 years posttransplantation were used when applying the calculators to BENEFIT and BENEFIT-EXT trial treatment arms. Results. MACE could be predicted using a 7-variable model. The area under the ROC curve was 0.738 in ALERT and 0.740 in PORT, indicating preserved discrimination. In PORT, the calibration of the model indicated significant underestimation of risk in decile 5 and 9. Total mortality could be predicted using a 6-variable model. The area under the ROC curve was 0.734 in ALERT and 0.721 in PORT, indicating preserved discrimination. In PORT, the calibration of the model indicated significant underestimation of risk in decile 7 and significant overestimation in the highest risk decile. In BENEFIT and BENEFIT-EXT trial, the calculator estimated that belatacept use may result in reduction in MACE (>20%) and mortality (similar to 18%-30%). Conclusion. The MACE and mortality risk calculators for prevalent RTRs have been externally validated and found suitable for generic risk stratification.

  • 85.
    Ståhle, Magnus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Friberg, Andrew
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ingvast, Sofie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Honkanen-Scott, Minna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Gyllenfjard, Sabina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Delorme, Bruno
    Sams, Audrey
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Preliminary Results From Evaluation of an Innovative, Closed, Automated, Continuous Media Renewal System for Human Islets of Langerhans2013In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 96, no 6, p. S145-S145Article in journal (Other academic)
  • 86.
    Ståhle, Magnus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Friberg, Andrew
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Commercial Enzymes for Islet Isolation: Integrity and Degradation Over Time and Temperature2013In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 96, no 6, p. S143-S143Article in journal (Other academic)
  • 87.
    Ståhle, Magnus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Honkanen-Scott, Minna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ingvast, Sofie
    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.
    Friberg, Andrew S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Human islet isolation processing times shortened by one hour: minimized incubation time between tissue harvest and islet purification2013In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 96, no 12, p. e91-e93Article in journal (Refereed)
  • 88.
    Ståhle, Magnus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Honkanen-Scott, Minna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ingvast, Sofie
    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.
    Friberg, Andrew S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Human Islet Isolation Processing Times Shortened By One Hour: Minimized Incubation Time Between Tissue Harvest and Islet Purification2013In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 96, no 12, p. E91-E93Article in journal (Refereed)
  • 89. Takemoto, Naohiro
    et al.
    Liu, Xibao
    Takii, Kento
    Teramura, Yuji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Iwata, Hiroo
    Transplantation of Co-aggregates of Sertoli Cells and Islet Cells Into Liver Without Immunosuppression2014In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 97, no 3, p. 287-293Article in journal (Refereed)
    Abstract [en]

    Background Transplantation of islets of Langerhans (islets) was used to treat insulin-dependent diabetes mellitus. However, islet grafts must be maintained by administration of immunosuppressive drugs, which can lead to complications in the long term. An approach that avoids immunosuppressive drug use is desirable. Methods Co-aggregates of Sertoli cells and islet cells from BALB/c mice that were prepared by the hanging drop method were transplanted into C57BL/6 mouse liver through the portal vein as in human clinical islet transplantation. Results The core part of the aggregates contained mainly Sertoli cells, and these cells were surrounded by islet cells. The co-aggregates retained the functions of both Sertoli and islet cells. When 800 co-aggregates were transplanted into seven C57BL/6 mice via the portal vein, six of seven recipient mice demonstrated quasi-normoglycemia for more than 100 days. Conclusions The hanging drop method is suitable for preparing aggregates of Sertoli and islet cells for transplantation. Notably, transplantation of these allogeneic co-aggregates into mice with chemically induced diabetes via the portal vein resulted in long-term graft survival without systemic immunosuppression.

  • 90.
    Tedesco-Silva, Helio
    et al.
    Division of Nephrology, Hospital do Rim, Universidade Federal de São Paulo, São Paulo, Brazil.
    Pascual, Julio
    Viklicky, Ondrej
    Basic-Jukic, Nikolina
    Cassuto, Elisabeth
    Kim, Dean Y
    Cruzado, Josep M
    Sommerer, Claudia
    Adel Bakr, Mohamed
    Garcia, Valter D
    Uyen, Huynh-Do
    Russ, Graeme
    Soo Kim, Myoung
    Kuypers, Dirk
    Buchler, Matthias
    Citterio, Franco
    Hernandez Gutierrez, Maria Pilar
    Bernhardt, Peter
    Chadban, Steve
    Department of Renal Medicine, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia.
    Safety of Everolimus With Reduced Calcineurin Inhibitor Exposure in De Novo Kidney Transplants: An Analysis From the Randomized TRANSFORM Study2019In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 103, no 9, p. 1953-1963Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The safety profiles of standard therapy versus everolimus with reduced-exposure calcineurin inhibitor (CNI) therapy using contemporary protocols in de novo kidney transplant recipients have not been compared in detail.

    METHODS: TRANSFORM was a randomized, international trial in which de novo kidney transplant patients were randomized to everolimus with reduced-exposure CNI (N = 1014) or mycophenolic acid (MPA) with standard-exposure CNI (N = 1012), both with induction and corticosteroids.

    RESULTS: Within the safety population (everolimus 1014, MPA 1012), adverse events with a suspected relation to study drug occurred in 62.9% versus 59.2% of patients given everolimus or MPA, respectively (P = 0.085). Hyperlipidemia, interstitial lung disease, peripheral edema, proteinuria, stomatitis/mouth ulceration, thrombocytopenia, and wound healing complications were more frequent with everolimus, whereas diarrhea, nausea, vomiting, leukopenia, tremor, and insomnia were more frequent in the MPA group. The incidence of viral infections (17.2% versus 29.2%; P < 0.001), cytomegalovirus (CMV) infections (8.1% versus 20.1%; P < 0.001), CMV syndrome (13.6% versus 23.0%, P = 0.044), and BK virus (BKV) infections (4.3% versus 8.0%, P < 0.001) were less frequent with everolimus. CMV infection was less common with everolimus versus MPA after adjusting for prophylaxis therapy in the D+/R- subgroup (P < 0.001). Study drug was discontinued more frequently due to rejection or impaired healing with everolimus, and more often due to BKV infection or BKV nephropathy with MPA.

    CONCLUSIONS: De novo everolimus with reduced-exposure CNI yielded a comparable incidence, though a distinctly different pattern, of adverse events versus current standard of care. Both regimens are safe and effective, yet their distinct profiles may enable tailoring for individual kidney transplant recipients.

  • 91. Teramura, Yuji
    et al.
    Takai, Madoka
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    A New Approach to Microencapsulation of Pancreatic Islets within Stable Ultra-Thin Membranes for Cell Transplantation2013In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 96, no 6, p. S67-S67Article in journal (Other academic)
  • 92. Thorsen, T.
    et al.
    Bennet, W.
    Olausson, M.
    Ericzon, B.
    Nowak, G.
    Duraj, Frans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Isoniemi, H.
    Rasmussen, A.
    Karlsen, T.
    Foss, A.
    The Use of Deceased Donors Over 75 Years in Liver Transplantation; a Nordic Collaborative Study.2014In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 98, p. 733-733Article in journal (Other academic)
  • 93.
    Thorsen, Trygve
    et al.
    Oslo Univ Hosp, Dept Transplantat Med, Sect Transplant Surg, Postboks 4950 Nydalen, N-0424 Oslo, Norway..
    Aandahl, Einar Martin
    Oslo Univ Hosp, Dept Transplantat Med, Sect Transplant Surg, Postboks 4950 Nydalen, N-0424 Oslo, Norway.;Univ Oslo, Biotechnol Ctr Oslo, Oslo, Norway.;Univ Oslo, Ctr Mol Med Norway, Nord EMBL Partnership, Oslo, Norway..
    Bennet, William
    Sahlgrens Univ Hosp, Dept Transplantat, Inst Clin Sci, Sahlgrenska Acad, Gothenburg, Sweden..
    Olausson, Michael
    Sahlgrens Univ Hosp, Dept Transplantat, Inst Clin Sci, Sahlgrenska Acad, Gothenburg, Sweden..
    Ericzon, Bo-Goran
    Karolinska Univ Hosp Huddinge, Div Transplantat Surg, Solna, Sweden..
    Nowak, Greg
    Karolinska Univ Hosp Huddinge, Div Transplantat Surg, Solna, Sweden..
    Duraj, Frans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Isoniemi, Helena
    Helsinki Univ Hosp, Transplantat & Liver Surg Clin, Helsinki, Finland..
    Rasmussen, Allan
    Univ Copenhagen, Rigshosp, Dept Surg Gastroenterol & Transplantat, DK-2100 Copenhagen, Denmark..
    Karlsen, Tom H.
    Oslo Univ Hosp, Div Canc Med Surg & Transplantat, Dept Transplantat Med, Norwegian PSC Res Ctr, N-0424 Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Foss, Aksel
    Oslo Univ Hosp, Dept Transplantat Med, Sect Transplant Surg, Postboks 4950 Nydalen, N-0424 Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Transplantation With Livers From Deceased Donors Older Than 75 Years2015In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 99, no 12, p. 2534-2542Article in journal (Refereed)
    Abstract [en]

    Background. The availability of donor organs limits the number of patients in need who are offered liver transplantation. Measures to expand the donor pool are crucial to prevent on-list mortality. The aim of this study was to evaluate the use of livers from deceased donors who were older than 75 years. Methods. Fifty-four patients who received a first liver transplant (D75 group) from 2001 to 2011 were included. Donor and recipient data were collected from the Nordic Liver Transplant Registry and medical records. The outcome was compared with a control group of 54 patients who received a liver graft from donors aged 20 to 49 years (D20-49 group). Median donor age was 77 years (range, 75-86 years) in the D75 group and 41 years (range, 20-49 years) in the D20-49 group. Median recipient age was 59 years (range, 31-73 years) in the D75 group and 58 years (range, 31-74 years) in the D20-49 group. Results. The 1-, 3-, and 5-year patient/graft survival values were 87/87%, 81/81%, and 71/67% for the D75 group and 88/87%, 75/73%, and 75/73% for the D20-49 group, respectively. Patient (P = 0.89) and graft (P = 0.79) survival did not differ between groups. The frequency of biliary complications was higher in the D75 group (29.6/13%, P = 0.03). Conclusions. Selected livers from donors over age 75 years should not be excluded based on age, which does not compromise patient or graft survival despite a higher frequency of biliary complications.

  • 94.
    Tjernberg, Jenny
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Ekdahl, Kristina N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Lambris, John D.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Acute antibody-mediated complement activation mediates lysis of pancreatic islets cells and may cause tissue loss in clinical islet transplantation2008In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 85, no 8, p. 1193-1199Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Clinical islet transplantation is associated with loss of transplanted islets necessitating tissue from more than one donor to obtain insulin independence. The instant blood-mediated inflammatory reaction (IBMIR) is one explanation to the tissue loss. Complement activation is an important cytotoxic component of the IBMIR, and in the present study, we have investigated this component in detail. METHODS: Isolated human islets were analyzed by large particle flow cytometry and confocal microscopy after incubation in human ABO-compatible hirudin-plasma. RESULTS: After incubation in plasma, the islets bound IgG and IgM, CIq, C4, C3 and C9. The binding of C3b/iC3b was evident already after 5 min. The binding of C3b/iC3b and the generation of C3a and sC5b-9 were inhibited by the complement inhibitor Compstatin. Lysis as reflected by propidium iodide (PI) staining and release of C-peptide was also inhibited by Compstatin. There were significant correlations between IgM/IgG versus C3b/iC3b and between sC5b-9 and C-peptide. CONCLUSION: The conclusion is that complement is activated by natural IgG and IgM antibodies already after 5 min. The complement activation leads to lysis of cells of the pancreatic islets. This very rapid reaction may be an essential entity of the damage induced by the IBMIR in clinical islet transplantation.

  • 95. Tokodai, Kazuaki
    et al.
    Goto, Masafumi
    Inagaki, Akiko
    Nakanishi, Wataru
    Ogawa, Norihiko
    Satoh, Kazushige
    Kawagishi, Naoki
    Sekiguchi, Satoshi
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Okada, Noriko
    Okada, Hidechika
    Satomi, Susumu
    Attenuation of Cross-Talk Between the Complement and Coagulation Cascades by C5a Blockade Improves Early Outcomes After Intraportal Islet Transplantation2010In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 90, no 12, p. 1358-1365Article in journal (Refereed)
    Abstract [en]

    Background. Complement 5a factor (C5a) elicits a broad range of proinflammatory effects, including chemotaxis of inflammatory cells and cytokine release. C5a is also linked to the coagulant activity in autoimmune diseases. Therefore, C5a most likely plays a crucial role in the instant blood-mediated inflammatory reaction. Methods. Intraportal transplantation of 2.5 islet equivalents/g of syngeneic rat islet grafts was performed in two groups of streptozotocin-induced diabetic rats: controls and C5a inhibitory peptide (C5aIP)-treated group. Results. The thrombin-antithrombin complex was significantly suppressed in the C5aIP group (P = 0.003), and both the curative rate and the glucose tolerance were significantly improved in the C5aIP group (P < 0.05 and P < 0.005, respectively). Expression of tissue factor on granulocytes in recipient livers was up-regulated 1 h after islet infusion (P < 0.0001), which was significantly suppressed by C5aIP (P < 0.005). However, C5aIP was unable to regulate tissue factor expression on isolated islets. Furthermore, no differences were detected between the groups, regarding infiltration of CD11b-positive cells and deposition of C5b-9 on the islet grafts. Conclusions. These data suggest that C5aIP attenuates cross-talk between the complement and coagulation cascades through suppressing up-regulation of tissue factor expression on leukocytes in recipient livers but not on islet grafts, a process leading to improvement in islet engraftment. Therefore, C5aIP in combination with conventional anticoagulants could be a strong candidate strategy to control the instant blood-mediated inflammatory reaction induced in clinical islet transplantation.

  • 96. Tydén, Gunnar
    et al.
    Donauer, Johannes
    Wadström, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Kumlien, Gunilla
    Wilpert, Jochen
    Nilsson, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Genberg, Helena
    Pisarski, Przemislaw
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Implementation of a Protocol for ABO-incompatible kidney transplantation--a three-center experience with 60 consecutive transplantations2007In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 83, no 9, p. 1153-1155Article in journal (Refereed)
    Abstract [en]

    Background. A new protocol for ABO-incompatible kidney transplantation has recently been introduced. We report here on the joint experience of the implementation in Stockholm and Uppsala, Sweden and Freiburg, Germany.

    Methods. The new protocol utilizes antigen-specific immunoadsorption to remove existing ABO-antibodies, rituximab, and intravenous immunoglobulin to prevent the rebound of antibodies, and conventional tacrolimus, mycophenolate-mofetil, and prednisolone immunosuppression. Sixty consecutive ABO-incompatible kidney transplantations were included in the study. The outcome is compared with the results of 274 ABO-compatible live donor transplantations performed during the same period.

    Results. Two of the ABO-incompatible grafts have been lost (non-compliance and death with functioning graft). All the remaining 58 grafts had good renal function at a follow-up of up to 61 months. We did not observe any late rebound of antibodies and there were no humoral rejections. Graft survival was 97% for the ABO-incompatible compared with 95% for the ABO-compatible. Patient survival was 98% in both groups. There was a significant variation in preoperative A/B-antibody titer between the centers, with a median 1:8 in Uppsala, median 1:32 in Stockholm and median 1:128 in Freiburg. More preoperative antibody adsorptions were therefore needed in Freiburg than in Stockholm and Uppsala.

    Conclusions. The new protocol was easily implemented and there were no graft losses that could be related to ABO-incompatibility. A significant inter-institutional variation in the measurement of anti-AB-antibodies was found, having a substantial impact on the number of immunoadsorptions and consequently on the total cost for the procedure. A standardized fluorescence-activated cell sorting technique for antibody quantification is much needed.

  • 97. Tydén, Gunnar
    et al.
    Ekberg, Henrik
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Mjörnstedt, Lars
    A randomized, double-blind, placebo-controlled study of single dose rituximab as induction in renal transplantation: a 3-year follow-up2012In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 94, no 3, p. e21-e22Article in journal (Refereed)
  • 98. Tydén, Gunnar
    et al.
    Genberg, Helena
    Tollemar, Jan
    Ekberg, Henrik
    Persson, Nils H.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Wadström, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Gäbel, Markus
    Mjörnstedt, Lars
    A randomized, doubleblind, placebo-controlled, study of single-dose rituximab as induction in renal transplantation2009In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 87, no 9, p. 1325-9Article in journal (Refereed)
    Abstract [en]

    We performed a prospective, double blind, randomized, placebo-controlled multicenter study on the efficacy and safety of rituximab as induction therapy, together with tacrolimus, mycophenolate mofetil, and steroids. The primary endpoint was defined as acute rejection, graft loss, or death during the first 6 months. Secondary endpoints were creatinine clearance, incidence of infections, and incidence of rituximab-related adverse event. RESULTS: We enrolled 140 patients (44 living donor and 96 deceased donor), and of those, 68 rituximab and 68 placebo patients fulfilled the study. In all the patients receiving rituximab, there was a complete depletion of CD19/CD20 cells, whereas there was no change in the number of CD19/CD20 cells in the placebo group. There were 10 treatment failures in the rituximab group versus 14 in the placebo group (P=0.348). There were eight rejection episodes in the rituximab group versus 12 in the placebo group (P=0.317) Creatinine clearance was 66+/-22 mL/min in the study group and 67+/-23 mL/min in the placebo group. There was no difference in the number of bacterial infections, cytomegalovirus infections, and BK virus infections or fungal infections. CONCLUSION: We performed a placebo-controlled study of rituximab induction in renal transplantation. There was a tendency toward fewer and milder rejections during the first 6 months in the rituximab group. Although induction with one dose of rituximab induced a complete depletion B cells, there was no increase in the incidence of infectious complications or leukopenia and it seems safe, therefore, to conduct further studies on the use of rituximab in transplantation.

  • 99. Tydén, Gunnar
    et al.
    Mjornstedt, Lars
    Ekberg, Henrik
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Authors' Reply to Letter by van den Hoogen and Hilbrands2010In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 89, no 10, p. 1295-1295Article in journal (Refereed)
  • 100.
    Ullsten, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Grapensparr, Liza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sandberg, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Schwann Cells Regulate Angiogenesis And Blood Vessel Structure In Native And Transplanted Pancreatic Islets2015In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 99, no 11, p. S75-S75Article in journal (Other academic)
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