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  • 1.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Preparatory Studies to Introduce Regulatory T Cells in Clinical Transplantation2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    National Category
    Immunology in the medical area
    Identifiers
    urn:nbn:se:uu:diva-220872 (URN)10.1016/j.jcyt.2014.05.016 (DOI)000342396800007 ()
    Available from: 2014-03-21 Created: 2014-03-21 Last updated: 2018-01-11Bibliographically approved
  • 2.
    Berglund, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Bengtsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Biglarnia, Alireza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Berglund, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Yamamoto, Shinji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    von Zur-Mühlen, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Lorant, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Screening of mortality in transplant patients using an assay for immune function2011In: Transplant Immunology, ISSN 0966-3274, E-ISSN 1878-5492, Vol. 24, no 4, p. 246-250Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: So far, the ImmuKnow Immune Cell Function Assay (Cylex, Inc., Columbia, MD, USA) has been used to assess risks of infection and rejection in transplant patients. We hypothesized that the ImmuKnow assay might be used for mortality screening in transplant patients overall. METHODS: In the period of February 2007 to December 2009, at the Uppsala University Hospital, 362 patients who received either kidney, kidney+pancreas, kidney+islet cells, liver or liver+kidney allografts were randomly screened using the ImmuKnow assay. All causes of mortality were compared between two groups: patients with at least one ImmuKnow assay below 175ng/mL and patients with all ImmuKnow assays from 175ng/mL and above. Subsequently, the frequency of rejection within thirty days of the ImmuKnow assay was compared between these two groups. RESULTS: The study included 1031 ImmuKnow assays obtained from the 362 patients. A total of 111 patients had at least one ImmuKnow below 175ng/mL and 251 patients had all their ImmuKnow assays from 175ng/mL and above. By January 31st 2010, 16 of 111 patients (14.4%) with at least one ImmuKnow assay below 175ng/mL were deceased, compared to 13 of 251 patients (5.2%) with all ImmuKnow assays from 175ng/mL and above (p=0.0053, Fisher's exact test). There was no difference in the frequency of rejection between the two groups (19.8% versus 17.5%, p=0.66). CONCLUSIONS: In addition to assessing relative risks of infection and rejection in transplant patients, the ImmuKnow assay may be used to identify patients with increased risk of short-term mortality. Transplant patients being highly overimmunosuppressed as assessed by the ImmuKnow assay do not seem to have a lower risk of short-term rejection.

  • 3.
    Berglund, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Bergqvist, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Lundqvist, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Magnusson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Sedigh, Amir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Bäckman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Biglarnia, Ali-Reza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Vascular reconstruction using allogeneic homografts in a renal transplant patient with pseudoaneurysm and infected vascular prosthesis2012In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 93, no 4, p. e15-e16Article in journal (Refereed)
  • 4.
    Berglund, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Karlsson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Biglarnia, Ali-Reza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Lorant, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Carlsson, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Obtaining regulatory T cells from uraemic patients awaiting kidney transplantation for use in clinical trials2013In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 173, no 2, p. 310-322Article in journal (Refereed)
    Abstract [en]

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

  • 5.
    Berglund, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Karlsson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Palanisamy, Senthilkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Carlsson, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Imaging the in vivo fate of human T cells following transplantation in immunoincompetent mice - Implications for clinical cell therapy trials2013In: Transplant Immunology, ISSN 0966-3274, E-ISSN 1878-5492, Vol. 29, no 1-4, p. 105-108Article in journal (Refereed)
    Abstract [en]

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

  • 6.
    Berglund, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Kinch, Amelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Edman, Elin
    Halmstad Hospital.
    Backlin, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Pauksens, Karlis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Expression of Intratumoral Forkhead Box Protein 3 in Posttransplant Lymphoproliferative Disorders: Clinical Features and Survival Outcomes2015In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 99, no 5, p. 1036-1042Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 7.
    Berglund, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lorant, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Schneider, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Carlsson, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Isolation, expansion and functional assessment of CD4+CD25+FoxP3+ regulatory T cells and Tr1 cells from uremic patients awaiting kidney transplantation2012In: Transplant Immunology, ISSN 0966-3274, E-ISSN 1878-5492, Vol. 26, no 1, p. 27-33Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 8.
    Berglund, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lindvall, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lubenow, Norbert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Green plasma2015In: Transfusion, ISSN 0041-1132, E-ISSN 1537-2995, Vol. 55, no 2, p. 245-245Article in journal (Other academic)
  • 9.
    Berglund, E.
    et al.
    Karolinsk Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Ljungdahl, M. Andersen
    Karolinsk Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Bogdanovic, D.
    Karolinsk Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Wadström, J.
    Karolinsk Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Weissenbacher, A.
    Innsbruck Med Univ, Ctr Operat Med, Innsbruck, Austria..
    Petruzzo, P.
    Hop Edouard Herriot, Dept Transplantat, Lyon, France..
    Schneeberger, S.
    Innsbruck Med Univ, Ctr Operat Med, Innsbruck, Austria..
    Clinical Significance of Alloantibodies in Hand Transplantation: Impact on Rejection and Functional Outcome2017In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 17, no S3, p. 240-240, article id 96Article in journal (Other academic)
  • 10. Berglund, Erik
    et al.
    Akcakaya, Pinar
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Karlsson, Fredrik
    Vukojevic, Vladana
    Lee, Linkiat
    Bogdanovic, Darko
    Lui, Weng-Onn
    Larsson, Catharina
    Zedenius, Jan
    Frobom, Robin
    Branstrom, Robert
    Functional role of the Ca2+-activated Cl- channel DOG1/TMEM16A in gastrointestinal stromal tumor cells2014In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 326, no 2, p. 315-325Article in journal (Refereed)
    Abstract [en]

    DOG1, a Ca2+-activated Cl- channel (CaCC), was identified in 2004 to be robustly expressed in gastrointestinal stromal tumors (GIST). It was rapidly included as a tumor marker in routine diagnostics, but the functional role remained unknown. CaCCs are important regulators of normal physiological functions, but also implicated in tumorigenesis, cancer progression, metastasis, cell migration, apoptosis, proliferation and viability in several malignancies. We therefore investigated whether DOG1 plays a role in the three latter in GIST by utilizing in vitro cell model systems. Confocal microscopy identified different subcellular localizations of DOG1 in imatinib-sensitive and imatinib-resistant cells. Electrophysiological studies confirmed that DOG1-specific pharmacological agents possess potent activating and inhibiting properties. Proliferation assays showed small effects up to 72 h, and flow cytometric analysis of adherent cells with 7-AAD/Annexin V detected no pharmacological effects on viable GIST cells. However, inhibition of DOG1 conveyed pro-apoptotic effects among early apoptotic imatinib-resistant cells. In conclusion, DOG1 generates Cl- currents in GIST that can be regulated pharmacologically, with small effects on cell viability and proliferation in vitro. Inhibition of DOG1 might act pro-apoptotic on some early apoptotic GIST cell populations. Further studies are warranted to fully illuminate the function of DOG1 and its potential as therapeutic target.

  • 11. Berglund, Erik
    et al.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Akcakaya, Pinar
    Ghaderi, Mehran
    Dare, Elisabetta
    Berggren, Per-Olof
    Aspinwall, Craig A.
    Lui, Weng-Onn
    Zedenius, Jan
    Larsson, Catharina
    Branstrom, Robert
    Evidence for intracellular calcium-regulated secretion in gastrointestinal stromal tumor.2013In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 73, no 8Article in journal (Other academic)
  • 12. Berglund, Erik
    et al.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Akcakaya, Pinar
    Ghaderi, Mehran
    Dare, Elisabetta
    Berggren, Per-Olof
    Kohler, Martin
    Aspinwall, Craig A.
    Lui, Weng-Onn
    Zedenius, Jan
    Larsson, Catharina
    Branstrom, Robert
    Evidence for Ca2+-regulated ATP release in gastrointestinal stromal tumors2013In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 319, no 8, p. 1229-1238Article in journal (Refereed)
    Abstract [en]

    Gastrointestinal stromal tumors (GISTs) are thought to originate from the electrically active pacemaker cells of the gastrointestinal tract. Despite the presence of synaptic-like vesicles and proteins involved in cell secretion it remains unclear whether GIST cells possess regulated release mechanisms. The GIST tumor cell line GIST882 was used as a model cell system, and stimulus-release coupling was investigated by confocal microscopy of cytoplasmic free Ca2+ concentration ([Ca(2+)1](i)), flow cytometry, and luminometric measurements of extracellular ATP. We demonstrate that GIST cells have an intact intracellular Ca2+-signaling pathway that regulates ATP release. Cell viability and cell membrane integrity was preserved, excluding ATP leakage due to cell death and suggesting active ATP release. The stimulus-secretion signal transduction is at least partly dependent on Ca2+ influx since exclusion of extracellular Ca2+ diminishes the ATP release. We conclude that measurements of ATP release in GISTs may be a useful tool for dissecting the signal transduction pathway, mapping exocytotic components, and possibly for the development and evaluation of drugs. Additionally, release of ATP from GISTs may have importance for tumor tissue homeostasis and immune surveillance escape.

  • 13.
    Berglund, Erik
    et al.
    Karolinska Univ Hosp, Dept Transplantat Surg, Stockholm, Sweden..
    Ljungdahl, Mette Andersen
    Karolinska Univ Hosp, Dept Transplantat Surg, Stockholm, Sweden..
    Bogdanovic, Darko
    Karolinska Univ Hosp, Dept Transplantat Surg, Stockholm, Sweden..
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Wadstrom, Jonas
    Karolinska Univ Hosp, Dept Transplantat Surg, Stockholm, Sweden..
    Weissenbacher, Anne-Marie
    Univ Oxford, Churchill Hosp, Oxford Transplant Ctr, Nuffield Dept Surg Sci, Oxford, England..
    Petruzzo, Palmina
    Hop Edouard Herriot, HCL, Dept Transplantat, Lyon, France..
    Schneeberger, Stefan
    Innsbruck Med Univ, Dept Visceral Transplant & Thorac Surg, Ctr Operat Med, Innsbruck, Austria..
    Clinical Significance Of Alloantibodies In Hand Transplantation - A Multicenter Study2017In: Transplant International, ISSN 0934-0874, E-ISSN 1432-2277, Vol. 30, p. 163-163Article in journal (Other academic)
  • 14.
    Berglund, Erik
    et al.
    Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Div Transplantat Surg, Stockholm, Sweden..
    Sellberg, Felix
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Assessing the purity of regulatory T cells: A humble reminder2017In: Cytotherapy, ISSN 1465-3249, E-ISSN 1477-2566, Vol. 19, no 2, p. 329-332Article in journal (Refereed)
  • 15.
    Bergström, Marcus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Joly, A. -L
    Seiron, P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Isringhausen, S.
    Modig, E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Andersson, J.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Immunological Profiling of Haemodialysis Patients and Young Healthy Individuals with Implications for Clinical Regulatory T Cell Sorting2015In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 81, no 5, p. 318-324Article in journal (Refereed)
    Abstract [en]

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

  • 16.
    Biglarnia, Alireza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Yamamoto, Shinji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Sedigh, Amir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Drachenberg, Cinthia
    Univ Maryland Hosp, Dept Pathol, Baltimore, MD 21201 USA..
    Wagner, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Sund, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    von Zur-Muehlen, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Impact of duodenal cuff inflammation on outcome after clinical pancreas transplantation - a survey of a comprehensive follow-up strategy including serial protocol biopsy of the duodenal cuff2015In: Xenotransplantation, ISSN 0908-665X, E-ISSN 1399-3089, Vol. 22, p. S15-S15Article in journal (Other academic)
  • 17.
    Fredriksson, Fanny
    et al.
    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.
    Sellberg, Felix
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Bowden, Tim
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Engstrand, T.
    Karolinska Univ Hosp, Dept Reconstruct Plast Surg, SE-17176 Stockholm, Sweden.;Karolinska Inst, SE-17176 Stockholm, Sweden..
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Engstrand Lilja, Helene
    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.
    Sutures impregnated with carbazate-activated polyvinyl alcohol reduce intraperitoneal adhesions2017In: Journal of Pediatric Surgery, ISSN 0022-3468, E-ISSN 1531-5037, Vol. 52, no 11, p. 1853-1858Article in journal (Refereed)
    Abstract [en]

    Background: Intraperitoneal adhesions cause significant morbidity. They occur after peritoneal trauma, which induces oxidative stress with production of inflammatory cytokines, peroxidized proteins (carbonyls) and lipids (aldehydes). This study aimed to investigate if carbazate-activated polyvinyl alcohol (PVAC), an aldehyde-carbonyl inhibitor, can reduce intraperitoneal adhesions in an experimental model.

    Material and methods: Male Sprague-Dawley rats (n = 110) underwent laparotomy, cecal abrasion and construction of a small bowel anastomosis. They either were treated with intraperitoneal instillation of PVAC or were sutured with PVAC-impregnated sutures. Thromboelastography analysis was performed using human blood and PVAC. The lipid peroxidation product malondialdehyde (MDA) and inflammatory cytokines IL-1 beta and IL-6 were quantified in peritoneal fluid. At day 7, bursting pressure of the anastomosis was measured and adhesions were blindly scored.

    Results: PVAC in human blood decreased the production of the fibrin-thrombocyte mesh without affecting the coagulation cascade. MDA, IL-1 beta and IL-6 were increased after 6 h without significant difference between the groups. PVAC-impregnated sutures reduced intraperitoneal adhesions compared to controls (p = 0.0406) while intraperitoneal instillation of PVAC had no effect. Anastomotic bursting pressure was unchanged.

    Conclusions: Intervention with an aldehyde-carbonyl inhibitor locally in the wound by PVAC-impregnated sutures might be a new strategy to reduce intraperitoneal adhesions.

  • 18. Fuchs, Anke
    et al.
    Gliwiński, Mateusz
    Grageda, Nathali
    Spiering, Rachel
    Abbas, Abul K
    Appel, Silke
    Bacchetta, Rosa
    Battaglia, Manuela
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Blazar, Bruce
    Bluestone, Jeffrey A
    Bornhäuser, Martin
    Ten Brinke, Anja
    Brusko, Todd M
    Cools, Nathalie
    Cuturi, Maria Cristina
    Geissler, Edward
    Giannoukakis, Nick
    Gołab, Karolina
    Hafler, David A
    van Ham, S Marieke
    Hester, Joanna
    Hippen, Keli
    Di Ianni, Mauro
    Ilic, Natasa
    Isaacs, John
    Issa, Fadi
    Iwaszkiewicz-Grześ, Dorota
    Jaeckel, Elmar
    Joosten, Irma
    Klatzmann, David
    Koenen, Hans
    van Kooten, Cees
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Kretschmer, Karsten
    Levings, Megan
    Marek-Trzonkowska, Natalia Maria
    Martinez-Llordella, Marc
    Miljkovic, Djordje
    Mills, Kingston H G
    Miranda, Joana P
    Piccirillo, Ciriaco A
    Putnam, Amy L
    Ritter, Thomas
    Roncarolo, Maria Grazia
    Sakaguchi, Shimon
    Sánchez-Ramón, Silvia
    Sawitzki, Birgit
    Sofronic-Milosavljevic, Ljiljana
    Sykes, Megan
    Tang, Qizhi
    Vives-Pi, Marta
    Waldmann, Herman
    Witkowski, Piotr
    Wood, Kathryn J
    Gregori, Silvia
    Hilkens, Catharien M U
    Lombardi, Giovanna
    Lord, Phillip
    Martinez-Caceres, Eva M
    Trzonkowski, Piotr
    Minimum Information about T Regulatory Cells: A Step toward Reproducibility and Standardization.2018In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, article id 1844Article in journal (Refereed)
    Abstract [en]

    Cellular therapies with CD4+ T regulatory cells (Tregs) hold promise of efficacious treatment for the variety of autoimmune and allergic diseases as well as posttransplant complications. Nevertheless, current manufacturing of Tregs as a cellular medicinal product varies between different laboratories, which in turn hampers precise comparisons of the results between the studies performed. While the number of clinical trials testing Tregs is already substantial, it seems to be crucial to provide some standardized characteristics of Treg products in order to minimize the problem. We have previously developed reporting guidelines called minimum information about tolerogenic antigen-presenting cells, which allows the comparison between different preparations of tolerance-inducing antigen-presenting cells. Having this experience, here we describe another minimum information about Tregs (MITREG). It is important to note that MITREG does not dictate how investigators should generate or characterize Tregs, but it does require investigators to report their Treg data in a consistent and transparent manner. We hope this will, therefore, be a useful tool facilitating standardized reporting on the manufacturing of Tregs, either for research purposes or for clinical application. This way MITREG might also be an important step toward more standardized and reproducible testing of the Tregs preparations in clinical applications.

  • 19.
    Hillerdal, Victoria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Boura, Vanessa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Jin, Chuan
    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 Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Engineering Regulatory Cells With a T Cell Receptor for Controlled Activation2014In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 22, p. S180-S180Article in journal (Other academic)
  • 20. Hulspas, R.
    et al.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Baecher-Allan, C.
    Villa-Komaroff, L.
    Sharpe, J.
    Production of Large-Scale Quantities of Rare Therapeutic Cells: a Progress Report2014In: Cytotherapy, ISSN 1465-3249, E-ISSN 1477-2566, Vol. 16, no 4, p. S111-S111Article in journal (Other academic)
  • 21. Hulspas, Ruud
    et al.
    Villa-Komaroff, Lydia
    Koksal, Erin
    Etienne, Kenol
    Rogers, Patricia
    Tuttle, Matt
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Sharpe, John
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Purification of regulatory T cells with the use of a fully enclosed high-speed microfluidic system2014In: Cytotherapy, ISSN 1465-3249, E-ISSN 1477-2566, Vol. 16, no 10, p. 1384-1389Article in journal (Refereed)
    Abstract [en]

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

  • 22.
    Massart, Annick
    et al.
    Univ Libre Bruxelles, Renal Unit, CUB Hop Erasme, Brussels, Belgium.;ULB, Med Genet Dept, Brussels, Belgium..
    Pallier, Annaick
    French Inst Hlth & Med Res, Joint Res Unit 1064, Nantes, France..
    Pascual, Julio
    Hosp del Mar, Nephrol, Barcelona, Spain..
    Viklicky, Ondrej
    Inst Clin & Expt Med, Dept Nephrol, Prague, Czech Republic..
    Budde, Klemens
    Charite Campus Mitte, Nephrol, Berlin, Germany..
    Spasovski, Goce
    Univ Dept Nephrol, Skopje, Macedonia..
    Klinger, Marian
    Nephrol & Transplantat Med, Wroclaw, Poland..
    Sever, Mehmet Sukru
    Istanbul Sch Med, Internal Med, Nephrol, Istanbul, Turkey..
    Sorensen, Soren Schwartz
    Rigshosp, Nephrol P, Copenhagen, Denmark..
    Hadaya, Karine
    Univ Hosp Geneva, Nephrol & Transplantat, Geneva, Switzerland..
    Oberbauer, Rainer
    Krankenhaus Elisabethinen Linz, Dept Med Nephrol Hypertens & Renal Transp 3, Linz, Austria..
    Dudley, Christopher
    North Bristol NHS Trust, Richard Bright Renal Ctr, Southmead Hosp, Bristol, Avon, England..
    De Fijter, Johan W.
    Leiden Univ, Med Ctr, Dept Med, Div Nephrol, Leiden, Netherlands..
    Yussim, Alexander
    Tel Aviv Univ, Sackler Sch Med, Dept Transplantat, Rabin Med Ctr, Tel Aviv, Israel..
    Hazzan, Marc
    CHU Lille, Nephrol Dept, Lille, France..
    Wekerle, Thomas
    Med Univ Vienna, Dept Surg, Sect Transplantat Immunol, Vienna, Austria..
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    De Biase, Consuelo
    Az Osped Univ Parma, UOS Trapianti Rene Pancreas, Ctr Trapianti Parma, Parma, Italy..
    Jose Perez-Saez, Maria
    Hosp del Mar, Nephrol, Barcelona, Spain..
    Muehlfeld, Anja
    Univ Hosp Aachen, Dept Nephrol, Aachen, Germany..
    Orlando, Giuseppe
    Wake Forest Sch Med, Dept Surg, Sect Transplantat, Winston Salem, NC USA..
    Clemente, Katia
    UOC Trapianti Organo, Laquila, Italy..
    Lai, Quirino
    UOC Trapianti Organo, Laquila, Italy..
    Pisani, Francesco
    UOC Trapianti Organo, Laquila, Italy..
    Kandus, Aljosa
    Univ Med Ctr Ljubljana, Renal Transplantat Ctr Ljubljana, Dept Nephrol, Ljubljana, Slovenia..
    Baas, Marije
    Radboudumc Nijmegen, Kidney Dis, Nijmegen, Netherlands..
    Bemelman, Frederike
    Acad Med Ctr, Dept Nephrol, Renal Transplant Unit, Amsterdam, Netherlands..
    Ponikvar, Jadranka Buturovic
    Univ Med Ctr Ljubljana, Renal Transplantat Ctr Ljubljana, Dept Nephrol, Ljubljana, Slovenia..
    Mazouz, Hakim
    CHU Sud, Serv Nephrol, Unite Transplantat Renale & Pancreat, Amiens, France..
    Stratta, Piero
    Amedeo Avogadro Univ, Dept Translat Med, AOU Maggiore Carita Novara, Novara, Italy..
    Subra, Jean-Francois
    CHU Angers, Serv Nephrol Dialyse Transplantat, Angers, France..
    Villemain, Florence
    CHU Angers, Serv Nephrol Dialyse Transplantat, Angers, France..
    Hoitsma, Andries
    Radboudumc Nijmegen, Kidney Dis, Nijmegen, Netherlands..
    Braun, Laura
    CHU Strasbourg, Hop Jour Nephrol, Serv Nephrol & Transplantat Renale, Nouvel Hop Civil, Strasbourg, France..
    Carmen Cantarell, Maria
    Hosp Univ Val dHebron, Nephrol, Barcelona, Spain..
    Colak, Hulya
    Tepecik Training & Res Hosp, Nephrol, Izmir, Turkey..
    Courtney, Aisling
    Belfast City Hosp, Reg Nephrol Unit, Belfast, Antrim, North Ireland..
    Frasca, Giovanni Maria
    AO Torrette Umberto I, Nefrol Dialisi & Trapianto Rene, Ancona, Italy..
    Howse, Matthew
    Royal Liverpool Univ Hosp, Nephrol Transplantat, Liverpool, Merseyside, England..
    Naesens, Maarten
    Univ Hosp Leuven, Dept Nephrol & Renal Transplantat, Leuven, Belgium..
    Reischig, Tomas
    Univ Hosp Plzen, Dept Internal Med, Nephrol Ward, Plzen, Czech Republic..
    Seron, Daniel
    Hosp Univ Val dHebron, Nephrol, Barcelona, Spain..
    Seyahi, Nurhan
    Istanbul Univ, Cerrahpasa Med Fac, Nephrol, Istanbul, Turkey..
    Tugmen, Cem
    Tepecik Training & Res Hosp, Gen Surg, Izmir, Turkey..
    Alonso Hernandez, Angel
    Univ Hosp, Serv Nefrol, La Coruna, Spain..
    Bena, Luboslav
    Univ Hosp Louis Pasteur Kosice, Transplant Ctr, Kosice, Slovakia..
    Biancone, Luigi
    Univ Turin, Dept Med Sci, Turin, Italy..
    Cuna, Vania
    Univ Bologna, St Orsola Univ Hosp, Dept Specialized Expt & Diagnost Med, Sect Nephrol,Nephrol Dialysis & Renal Transplant, Bologna, Italy..
    Diaz-Corte, Carmen
    HUCA, Nephrol, Oviedo, Spain..
    Dufay, Alexandre
    Hop Victor Provo, Serv Nephrol, Roubaix, France..
    Gaasbeek, Andre
    LUMC, Nierziekten, Leiden, Netherlands..
    Garnier, Arnaud
    Hop Enfants, Nephrol Med Interne Hypertens Pediat, Toulouse, France..
    Gatault, Philippe
    CHRU, Serv Nephrol Immunoclin, Hop Bretonneau, Tours, France..
    Gentil Govantes, Miguel Angel
    Hosp Univ Virgen del Rocio, Unidad Gest Clin Urol & Nefrol, Seville, Spain..
    Glowacki, Francois
    Univ Hosp Lille, Dept Nephrol, Lille, France..
    Gross, Oliver
    Univ Med Gottingen, Dept Nephrol & Rheumatol, Gottingen, Germany..
    de Ligny, Bruno Hurault
    CHRU Ave Georges Clemenceau, Serv Nephrol, Caen, France..
    Huynh-Do, Uyen
    Univ Hosp Bern, Inselspital, Div Nephrol Hypertens & Clin Pharmacol, Bern, Switzerland..
    Janbon, Benedicte
    CHU Grenoble, Transplantat Renale, Grenoble, France..
    Antonio Jimenez del Cerro, Luis
    Hosp Gen Univ Alicante, Serv Nefrol, Alicante, Spain..
    Keller, Frieder
    Univ Hosp Ulm, Internal Med 1, Nephrol, Ulm, Germany..
    La Manna, Gaetano
    Univ Bologna, St Orsola Univ Hosp, Dept Specialized Expt & Diagnost Med, Sect Nephrol,Nephrol Dialysis & Renal Transplant, Bologna, Italy..
    Lauzurica, Ricardo
    Hosp Badalona Germans Trias & Pujol, Nephrol, Badalona, Barcelona, Spain..
    De Sagazan, Herve Le Monies
    Hop Victor Provo, Serv Nephrol, Roubaix, France..
    Thaiss, Friedrich
    Univ Hosp Hamburg Eppendorf UKE, Hamburg, Germany..
    Legendre, Christophe
    Univ Paris 05, Paris, France.;Hop Necker Enfants Malad, Paris, France..
    Martin, Severine
    Hop Robert Boulin, Serv Hemodialyse & Nephrol, Libourne, France..
    Moal, Marie-Christine
    CHRU Brest, Serv Nephrol, Brest, France..
    Noel, Christian
    Univ Hosp Lille, Dept Nephrol, Lille, France..
    Pillebout, Evangeline
    Hop St Louis, Nephrol Unit, Paris, France..
    Piredda, Gian Benedetto
    Kidney Transplant Az Osp G Brotzu, Kidney Dis, Cagliari, Italy..
    Ramirez Puga, Ana
    Hosp Univ Insular Gran Canaria, Serv Nefrol, Las Palmas Gran Canaria, Spain..
    Sulowicz, Wladyslaw
    Univ Hosp Krakow, Dept Nephrol, Krakow, Poland..
    Tuglular, Serhan
    Marmara Sch Med Hastanesi, Nephrol, Istanbul, Turkey..
    Prokopova, Michaela
    Inst Clin & Expt Med, Dept Nephrol, Prague, Czech Republic..
    Chesneau, Melanie
    Nantes Univ Hosp, Inst Transplantat Urol & Nephrol, Nantes, France..
    Le Moine, Alain
    Univ Libre Bruxelles, Renal Unit, CUB Hop Erasme, Brussels, Belgium..
    Guerif, Pierrick
    Nantes Univ Hosp, Inst Transplantat Urol & Nephrol, Nantes, France..
    Soulillou, Jean-Paul
    French Inst Hlth & Med Res, Joint Res Unit 1064, Nantes, France.;Nantes Univ Hosp, Inst Transplantat Urol & Nephrol, Nantes, France.;Univ Nantes, Fac Med, Nantes, France..
    Abramowicz, Marc
    ULB, Med Genet Dept, Brussels, Belgium.;ULB, IRIBHM, Brussels, Belgium..
    Giral, Magali
    French Inst Hlth & Med Res, Joint Res Unit 1064, Nantes, France.;Nantes Univ Hosp, Inst Transplantat Urol & Nephrol, Nantes, France.;Univ Nantes, Fac Med, Nantes, France..
    Racape, Judith
    ULB, Res Ctr Epidemiol Biostat & Clin Res, Sch Publ Hlth, Brussels, Belgium..
    Maggiore, Umberto
    Az Osped Univ Parma, UOS Trapianti Rene Pancreas, Ctr Trapianti Parma, Parma, Italy..
    Brouard, Sophie
    French Inst Hlth & Med Res, Joint Res Unit 1064, Nantes, France.;Nantes Univ Hosp, Inst Transplantat Urol & Nephrol, Nantes, France.;Univ Nantes, Fac Med, Nantes, France..
    Abramowicz, Daniel
    Univ Ziekenhuis Antwerp, Nephrol Renal Transplantat Dept, Antwerp, Belgium.;Univ Libre Bruxelles, Brussels, Belgium..
    The DESCARTES-Nantes survey of kidney transplant recipients displaying clinical operational tolerance identifies 35 new tolerant patients and 34 almost tolerant patients2016In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 31, no 6, p. 1002-1013Article in journal (Refereed)
    Abstract [en]

    Background. Kidney recipients maintaining a prolonged allograft survival in the absence of immunosuppressive drugs and without evidence of rejection are supposed to be exceptional. The ERA-EDTA-DESCARTES working group together with Nantes University launched a European-wide survey to identify new patients, describe them and estimate their frequency for the first time. Methods. Seventeen coordinators distributed a questionnaire in 256 transplant centres and 28 countries in order to report as many 'operationally tolerant' patients (TOL; defined as having a serum creatinine <1.7 mg/dL and proteinuria <1 g/day or g/g creatinine despite at least 1 year without any immunosuppressive drug) and 'almost tolerant' patients (minimally immunosuppressed patients (MIS) receiving low-dose steroids) as possible. We reported their number and the total number of kidney transplants performed at each centre to calculate their frequency. Results. One hundred and forty-seven questionnaires were returned and we identified 66 TOL (61 with complete data) and 34 MIS patients. Of the 61 TOL patients, 26 were previously described by the Nantes group and 35 new patients are presented here. Most of them were noncompliant patients. At data collection, 31/35 patients were alive and 22/31 still operationally tolerant. For the remaining 9/31, 2 were restarted on immunosuppressive drugs and 7 had rising creatinine of whom 3 resumed dialysis. Considering all patients, 10-year death-censored graft survival post-immunosuppression weaning reached 85% in TOL patients and 100% in MIS patients. With 218 913 kidney recipients surveyed, cumulative incidences of operational tolerance and almost tolerance were estimated at 3 and 1.5 per 10 000 kidney recipients, respectively. Conclusions. In kidney transplantation, operational tolerance and almost tolerance are infrequent findings associated with excellent long-term death-censored graft survival.

  • 23.
    Sellberg, Felix
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Berglund, Erik
    Karolinska Univ Hosp, Karolinska Inst, CLINTEC, Dept Transplantat Surg,Div Transplantat Surg, Stockholm, Sweden..
    Ronaghi, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Strandberg, Gabriel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Löf, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Sommar, Pehr
    Karolinska Inst, Sect Plast Surg, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Lubenow, Norbert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Knutson, Folke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Composition of growth factors and cytokines in lysates obtained from fresh versus stored pathogen-inactivated platelet units2016In: Transfusion and apheresis science, ISSN 1473-0502, E-ISSN 1878-1683, Vol. 55, no 3, p. 333-337Article in journal (Refereed)
    Abstract [en]

    Background: Platelet lysate is a readily available source of growth factors, and other mediators, which has been used in a variety of clinical applications. However, the product remains poorly standardized and the present investigation evaluates the composition of platelet lysate obtained from either fresh or stored pathogen-inactivated platelet units.

    Materials and Methods: Platelet pooled units (n = 10) were obtained from healthy blood donors and tested according to standard procedures. All units were pathogen inactivated using amotosalen hydrochloride and UVA exposure. Platelet lysate was subsequently produced at two separate time-points, either from fresh platelet units or after 5 days of storage, by repeated freeze-thaw cycles. The following mediators were determined at each time point: EGF, FGF-2, VEGF, IGF-1, PDGF-AB/BB, BMP-2, PF4, TGF-beta isoform 1, IL-1(i, IL-2, IL-6, IL-10, IL-12p70, 1L-17A, TNF-alpha, and IFN-gamma.

    Results: The concentration of growth factors and cytokines was affected by time in storage. Notably, TGF-beta, PDGF-AB/BB, and PF4 showed an increase of 27.2% (p < 0.0001), 29.5% (p = 0.04) and 8.2% (p = 0.0004), respectively. A decrease was seen in the levels of IGF-1 and FGF-2 with 22% (p = 0.041) and 11% (p = 0.01), respectively. Cytokines were present only in very low concentrations and all other growth factors remained stable with time in storage.

    Conclusion: The composition of mediators in platelet lysate obtained from pathogen inactivated platelet units differs when produced from fresh and stored platelet units, respectively. This underscores the need for further standardization and optimization of this important product, which potentially may influence the clinical effects.

  • 24.
    Sellberg, Felix
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ronaghi, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Knutson, Folke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Inflammatory cytokines in serum samples of healthy blood donors2016In: Transfusion and apheresis science, ISSN 1473-0502, E-ISSN 1878-1683, Vol. 55, no 2, p. 246-247Article in journal (Refereed)
  • 25.
    Stenwall, Per-Anton
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Bergström, Marcus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Seiron, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sellberg, Felix
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Olsson, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Knutson, Folke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Improving the anti-inflammatory effect of serum eye drops using allogeneic serum permissive for regulatory T cell induction2015In: Acta Ophthalmologica, ISSN 1755-375X, E-ISSN 1755-3768, Vol. 93, no 7, p. 654-657Article in journal (Refereed)
    Abstract [en]

    PurposeTo investigate the cytokine composition and anti-inflammatory effects of allogeneic serum preparations for improved use as serum eye drops. MethodsSerum of 15 healthy blood donors was extensively screened for cytokines, including IL-1, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12p70, IL-13, IL-15, 1L-17A, E and F, IL-21, IL-22, IL-23, IL-27, IL-28A, IL-31, IL-33, granulocyte macrophage colony-stimulating factor (GM-CSF), chemokine ligand 20 (CCL20), tumour necrosis factor (TNF)- and TNF-, interferon (IFN)- and transforming growth factor (TGF)-. The levels of cytokines were assessed before and after heat-induced inactivation. Individual serum preparations were tested for their anti-inflammatory effect using an invitro test to differentiate effector T lymphocytes into anti-inflammatory regulatory T cells. ResultsThe anti-inflammatory cytokine TGF- was readily detected in the serum of all blood donors and was only modestly affected by heat-induced inactivation. Serum containing high amounts of TGF- was more effective at inducing anti-inflammatory regulatory T cells. The serum of one healthy blood donor displayed high levels of inflammatory cytokines. ConclusionWe propose that serum used as eye drops is screened for its cytokine content, making it possible to correlate the composition to the clinical outcome. Based on the findings in this study, tailored serum eye drops produced from allogeneic donors may provide increased anti-inflammatory effects. This may be superior to autologous serum eye drops, which in many cases are retrieved from patients with inflammatory diseases.

  • 26.
    Strandberg, Gabriel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Sellberg, Felix
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Sommar, Pehr
    Karolinska Inst.
    Ronaghi, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lubenow, Norbert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Knutson, Folke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Standardizing the freeze-thaw preparation of growth factors from platelet lysate2017In: Transfusion, ISSN 0041-1132, E-ISSN 1537-2995, Vol. 57, no 4, p. 1058-1065Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Over the past decades, the focus on the regenerative properties of platelets (PLTs) has intensified and many PLT-derived growth factors are readily used in medical settings. A general lack of standardization in the preparation of these growth factors remains, however, and this study therefore examines the dynamics of growth factors throughout the freeze-thaw procedure.

    STUDY DESIGN AND METHODS: Plateletpheresis (PA) and PLT-poor plasma (PPP) samples were collected from 10 healthy donors. PA was lysed to produce PLT lysate (PL) for 1, 3, 5, 10, and 30 freeze-thaw cycles. The resulting growth factor and cytokine concentrations from PPP, PA, and PL of different cycles were analyzed and compared using enzyme-linked immunosorbent assay and multiplex bead assays.

    RESULTS: PL produced by the freeze-thaw procedure resulted in approximately four-to 10-fold enrichment of transforming growth factor-b1, epidermal growth factor, PLT-derived growth factor (PDGF)-AB/BB, PLT factor-4, and fibroblast growth factor-2. The increase in concentrations plateaued at Cycles 3 and 5 and in some cases declined with further cycles. The concentrations of insulin-like growth factor-1, hepatocyte growth factor, vascular endothelial growth factor, and bone morphogenetic protein-2 in PL were essentially comparable to those in PPP.

    CONCLUSION: Using the freeze-thaw method, optimal preparation of PL with regard to the concentration of growth factors was achieved at Cycles 3 to 5. Based on our findings, the clinical significance of using a greater number of cycles is likely limited.

  • 27.
    Trzonkowski, Piotr
    et al.
    Med Univ Gdansk, Dept Clin Immunol & Transplantol, PL-80952 Gdansk, Poland..
    Bacchetta, Rosa
    Stanford Sch Med, Dept Pediat Stem Cell Transplantat & Regenerat Me, Stanford, CA USA..
    Battaglia, Manuela
    Ist Sci San Raffaele, IRCCS, DRI, I-20132 Milan, Italy..
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Bohnenkamp, Hermann Richard
    Miltenyi Biotec GmbH, Clin Business, D-51429 Bergisch Gladbach, Germany..
    ten Brinke, Anja
    Sanquin Blood Supply, Div Res, Dept Immunopathol, NL-1066 CX Amsterdam, Netherlands.;Univ Amsterdam, Acad Med Ctr, Landsteiner Lab, NL-1105 AZ Amsterdam, Netherlands..
    Bushell, Andrew
    Univ Oxford, John Radcliffe Hosp, Nuffield Dept Surg Sci, Oxford OX3 9DU, England..
    Cools, Nathalie
    Univ Antwerp, Antwerp Univ Hosp UZA, Fac Med & Hlth Sci, Vaccine & Infect Dis Inst,Lab Expt Hematol, B-2650 Edegem, Belgium..
    Geissler, Edward K.
    Univ Hosp Regensburg, Dept Surg, Div Expt Surg, D-93053 Regensburg, Bavaria, Germany..
    Gregori, Silvia
    Ist Sci San Raffaele, IRCCS, Div Regenerat Med Stem Cells & Gene Therapy, San Raffaele Telethon Inst Gene Therapy HSR TIGET, I-20132 Milan, Italy..
    van Ham, S. Marieke
    Sanquin Blood Supply, Div Res, Dept Immunopathol, NL-1066 CX Amsterdam, Netherlands.;Univ Amsterdam, Acad Med Ctr, Landsteiner Lab, NL-1105 AZ Amsterdam, Netherlands..
    Hilkens, Catharien
    Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England..
    Hutchinson, James A.
    Univ Hosp Regensburg, Dept Surg, Div Expt Surg, D-93053 Regensburg, Bavaria, Germany..
    Lombardi, Giovanna
    Kings Coll London, Guys Hosp, Ctr Transplantat, MRC, London SE1 9RT, England..
    Madrigal, J. Alejandro
    UCL, Anthony Nolan Res Inst, London NW3 2QG, England..
    Marek-Trzonkowska, Natalia
    Med Univ Gdansk, Dept Family Med, PL-80210 Gdansk, Poland..
    Martinez-Caceres, Eva M.
    Univ Autonoma Barcelona, Germans Trias & Pujol Univ Hosp, Dept Cellular Biol Physiol & Immunol, Div Immunol, Barcelona 08916, Spain..
    Roncarolo, Maria Grazia
    Ist Sci San Raffaele, IRCCS, Div Regenerat Med Stem Cells & Gene Therapy, San Raffaele Telethon Inst Gene Therapy HSR TIGET, I-20132 Milan, Italy.;Stanford Sch Med, Dept Pediat Stem Cell Transplantat & Rege, Stanford, CA USA..
    Sanchez-Ramon, Silvia
    Hosp Clin San Carlos, Dept Inmunol Clin, E-28040 Madrid, Spain..
    Saudemont, Aurore
    UCL, Anthony Nolan Res Inst, London NW3 2QG, England..
    Sawitzki, Birgit
    Charite, AG Transplantat Toleranz, Inst Med Imunol, D-13353 Berlin, Germany..
    Hurdles in therapy with regulatory T cells2015In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 7, no 304, article id 304ps18Article in journal (Refereed)
    Abstract [en]

    Improper activation of the immune system contributes to a variety of clinical conditions, including autoimmune and allergic diseases as well as solid organ and bone marrow transplantation. One approach to counteract this activation is through adoptive therapy with regulatory T cells (T-regs). Efforts to manufacture these cells have led to good maunfacturing practice-compliant protocols, and T-reg products are entering early clinical trials. Here, we report the stance of the European Union Cooperation in Science and Technology Action BM1305, "Action to Focus and Accelerate Cell-based Tolerance-inducing Therapies-A FACTT," which identifies hurdles hindering T-reg clinical applications in Europe and provides possible solutions.

  • 28.
    Von Zur-Mühlen, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Yamamoto, Shinji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Wadstrom, Jonas
    Single-centre long-term follow-up of live kidney donors demonstrates preserved kidney function but the necessity of a structured lifelong follow-up2014In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 119, no 3, p. 236-241Article in journal (Refereed)
    Abstract [en]

    Background. The increase of live kidney donation (LKD) demands that we scrutinize its long-term consequences. Socialized medicine in Sweden has allowed us to survey long-term consequences of LKD with a high response rate. Methods. Between 1974 and 2008, 455 LKDs were performed; 28 donors were deceased and 14 had moved abroad at the time of the survey. Of the remaining 413, 96% agreed to participate in a retrospective study with laboratory testing and answering a questionnaire. Results. Mean age at donation was 49 +/- 10 years, and the mean time since nephrectomy was 11 +/- 7 years (range 1-33). No death was of renal cause. S-creatinine at follow-up was 93 +/- 18 mu mol/L, 28% had treated hypertension, of whom only 52% had BP <140/90. Eleven per cent had spot microalbuminuria, and 1% were diagnosed with diabetes mellitus. Seventy-one per cent had check-ups at least every second year, but 14% had no check-ups. Eighty per cent would be willing to donate again if it were possible, and only 3% regretted the donation. Conclusion. Renal function is well preserved in the long term after donation, no case of end-stage renal disease was identified, and a large majority of our donors would donate again if it were possible. Although rates of microalbuminuria and hypertension were at expected levels, a significant number of donors demonstrated elevated blood pressure levels and inadequate antihypertensive treatment. A relatively large number of donors did not receive regular check-ups. Both of these issues demonstrate the need for a better-structured lifelong follow-up.

  • 29. Wadstrom, J.
    et al.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Yamamoto, S.
    von Zur-Muhlen, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Single Centre Long-Term Follow-Up of Live Kidney Donors Demonstrates Preserved Kidney Function But the Necessity of a Structured Life-Long Follow-Up2014In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 98, p. 494-494Article in journal (Other academic)
  • 30. Wadstrom, J.
    et al.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Yamamoto, S.
    von zur-Muhlen, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Single Centre Long-Term Follow-Up of Live Kidney Donors Demonstrates Preserved Kidney Function But the Necessity of a Structured Life-Long Follow-Up2014In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 14, p. 494-494Article in journal (Other academic)
  • 31.
    Watanabe, M.
    et al.
    Karolinska Inst, Transplantat Surg, Stockholm, Sweden..
    Kumagai-Braesch, M.
    Karolinska Inst, Transplantat Surg, Stockholm, Sweden..
    Thunberg, S.
    Karolinska Inst, Lab Med, Stockholm, Sweden..
    Henrikson, J.
    Karolinska Inst, Transplantat Surg, Stockholm, Sweden..
    Sellberg, Felix
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lundgren, T.
    Karolinska Inst, Transplantat Surg, Stockholm, Sweden..
    Yao, M. H.
    Karolinska Inst, Transplantat Surg, Stockholm, Sweden..
    Jorns, C.
    Karolinska Inst, Transplantat Surg, Stockholm, Sweden..
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Berglund, E.
    Karolinska Inst, Transplantat Surg, Stockholm, Sweden..
    Ericzon, B-G
    Karolinska Inst, Transplantat Surg, Stockholm, Sweden..
    Ex vivo generation of alloantigen-specific T regulatory cells using selective T-cell costimulation blockade2016In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 46, p. 125-125Article in journal (Other academic)
  • 32.
    Watanabe, Masaaki
    et al.
    Karolinska Inst, Div Transplantat Surg CLINTEC, S-10401 Stockholm, Sweden..
    Kumagai-Braesch, Makiko
    Karolinska Inst, Div Transplantat Surg CLINTEC, S-10401 Stockholm, Sweden..
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Thunberg, Sara
    Karolinska Inst, Lab Med, S-10401 Stockholm, Sweden..
    Jorns, Carl
    Karolinska Inst, Div Transplantat Surg CLINTEC, S-10401 Stockholm, Sweden..
    Henriksson, Jarmo
    Karolinska Inst, Div Transplantat Surg CLINTEC, S-10401 Stockholm, Sweden..
    Lundgren, Torbjorn
    Karolinska Inst, Div Transplantat Surg CLINTEC, S-10401 Stockholm, Sweden..
    Sellberg, Felix
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Berglund, Erik
    Karolinska Inst, Div Transplantat Surg CLINTEC, S-10401 Stockholm, Sweden..
    Ericzon, Bo-Goran
    Karolinska Inst, Div Transplantat Surg CLINTEC, S-10401 Stockholm, Sweden..
    Ex-Vivo Generation Of Alloantigen-Specific Regulatory T Cells Using Selective T-Cell Costimulation Blockade: A Comparison Study Between Anti-Cd80/86 Mabs And CTLA4-Ig2015In: Transplant International, ISSN 0934-0874, E-ISSN 1432-2277, Vol. 28, p. 219-219Article in journal (Other academic)
  • 33.
    Watanabe, Masaaki
    et al.
    Karolinska Inst, CLINTEC, Div Transplantat Surg, Stockholm, Sweden..
    Kumagai-Braesch, Makiko
    Karolinska Inst, CLINTEC, Div Transplantat Surg, Stockholm, Sweden..
    Yao, Ming
    Karolinska Inst, CLINTEC, Div Transplantat Surg, Stockholm, Sweden..
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Jorns, Carl
    Karolinska Inst, CLINTEC, Div Transplantat Surg, Stockholm, Sweden..
    Thunberg, Sara
    Karolinska Inst, Dept Clin Immunol, S-10401 Stockholm, Sweden..
    Lind-Enoksson, Sara
    Karolinska Inst, Dept Clin Immunol, S-10401 Stockholm, Sweden..
    Henrikson, Jarmo
    Karolinska Inst, CLINTEC, Div Transplantat Surg, Stockholm, Sweden..
    Lundgren, Torbjorn
    Karolinska Inst, CLINTEC, Div Transplantat Surg, Stockholm, Sweden..
    Sellberg, Felix
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Berglund, Erik
    Karolinska Inst, CLINTEC, Div Transplantat Surg, Stockholm, Sweden..
    Ericzon, Bo-Goran
    Karolinska Inst, CLINTEC, Div Transplantat Surg, Stockholm, Sweden..
    Ex Vivo Generation of Alloantigen-Specific T Regulatory Cells using Selective T-Cell Co-Stimulation Blockade2015In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 99, no 11, p. S47-S47Article in journal (Other academic)
  • 34.
    Westman, Gabriel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Widen, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lidehall, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Eriksson, Britt-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Increased Inflammatory Response in Cytomegalovirus Seropositive Patients with Alzheimer's Disease2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 5, p. e96779-Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease (AD) has been associated with increased local inflammation in the affected brain regions, and in some studies also with elevated levels of proinflammatory cytokines in peripheral blood. Cytomegalovirus (CMV) is known to promote a more effector-oriented phenotype in the T-cell compartment, increasing with age. The aim of this study was to investigate the inflammatory response of peripheral blood mononuclear cells (PBMCs) from AD patients and non-demented (ND) controls. Using a multiplex Luminex xMAP assay targeting GM-CSF, IFN-gamma, IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-8, IP-10 and TNF-alpha, cytokine profiles from PBMCs were analysed after stimulation with anti-CD3/CD28 beads, CMV pp65 peptide mix or amyloid beta (A beta) protofibrils, respectively. CMV seropositive AD subjects presented with higher IFN-gamma levels after anti-CD3/ CD28 and CMV pp65 but not after Ab stimulation, compared to CMV seropositive ND controls. When analysing IFN-gamma response to anti-CD3/CD28 stimulation on a subgroup level, CMV seropositive AD subjects presented with higher levels compared to both CMV seronegative AD and CMV seropositive ND subjects. Taken together, our data from patients with clinically manifest AD suggest a possible role of CMV as an inflammatory promoter in AD immunology. Further studies of AD patients at earlier stages of disease, could provide better insight into the pathophysiology.

1 - 34 of 34
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