| 1. |
- Senage, T., et al.
(författare)
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The role of antibody responses against glycans in bioprosthetic heart valve calcification and deterioration
- 2022
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 28, s. 283-294
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Tidskriftsartikel (refereegranskat)abstract
- Bioprosthetic heart valves (BHVs) are commonly used to replace severely diseased heart valves but their susceptibility to structural valve degeneration (SVD) limits their use in young patients. We hypothesized that antibodies against immunogenic glycans present on BHVs, particularly antibodies against the xenoantigens galactose-alpha 1,3-galactose (alpha Gal) and N-glycolylneuraminic acid (Neu5Gc), could mediate their deterioration through calcification. We established a large longitudinal prospective international cohort of patients (n = 1668, 34 +/- 43 months of follow-up (0.1-182); 4,998 blood samples) to investigate the hemodynamics and immune responses associated with BHVs up to 15 years after aortic valve replacement. Early signs of SVD appeared in <5% of BHV recipients within 2 years. The levels of both anti-alpha Gal and anti-Neu5Gc IgGs significantly increased one month after BHV implantation. The levels of these IgGs declined thereafter but anti-alpha Gal IgG levels declined significantly faster in control patients compared to BHV recipients. Neu5Gc, anti-Neu5Gc IgG and complement deposition were found in calcified BHVs at much higher levels than in calcified native aortic valves. Moreover, in mice, anti-Neu5Gc antibodies were unable to promote calcium deposition on subcutaneously implanted BHV tissue engineered to lack alpha Gal and Neu5Gc antigens. These results indicate that BHVs manufactured using donor tissues deficient in alpha Gal and Neu5Gc could be less prone to immune-mediated deterioration and have improved durability. In a large cohort of patients who underwent aortic valve replacement, antibody responses to glycans present in bioprosthetic heart valves, notably galactose-alpha 1,3-galactose and N-glycolylneuraminic acid, were implicated in valve calcification and deterioration.
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| 2. |
- Curtis, J M, et al.
(författare)
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Electron ionization-tandem mass spectrometry of glycosphingolipids. I: The identiftcation of compound-specific sequence ions in the collision-induced dissociation spectra of the immonium ions of two isomeric hexaglycosylceramides.
- 1992
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Ingår i: Journal of the American Society for Mass Spectrometry. - : American Chemical Society (ACS). - 1044-0305. ; 3:4, s. 353-9
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Tidskriftsartikel (refereegranskat)abstract
- A permethylated-reduced hexaglycosylceramide in a complex glycolipid mixture isolated from a unique human tissue has been identified by using tandem mass spectrometry (MS/MS). The mass spectrum of this glycolipid mixture, obtained by using in-beam electron ionization, is very complex, and fragment ions derived from the hexaglycosylceramide cannot be distinguished from other ions. Tandem mass spectrometry using a four-sector mass spectrometer gave the mass spectrum of the immonium ion of the permethylated-reduced hexaglycosykeramide (m / z 1645.8), which is characteristic of its structure. Comparison of this MS/MS spectrum with those of two similarly derivatized blood group hexaglycosylceramide isomers permitted identification of the unknown glycolipid structure.
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| 4. |
- Kuna, Vijay Kumar, 1987, et al.
(författare)
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Successful tissue engineering of competent allogeneic venous valves
- 2015
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Ingår i: Journal of Vascular Surgery. - : Elsevier Inc.. - 0741-5214. ; 3:4, s. 421-430
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Tidskriftsartikel (refereegranskat)abstract
- Objective The purpose of this study was to evaluate whether tissue-engineered human allogeneic vein valves have a normal closure time (competency) and tolerate reflux pressure in vitro. Methods Fifteen human allogeneic femoral vein segments containing valves were harvested from cadavers. Valve closure time and resistance to reflux pressure (100 mm Hg) were assessed in an in vitro model to verify competency of the vein valves. The segments were tissue engineered using the technology of decellularization (DC) and recellularization (RC). The decellularized and recellularized vein segments were characterized biochemically, immunohistochemically, and biomechanically. Results Four of 15 veins with valves were found to be incompetent immediately after harvest. In total, 2 of 4 segments with incompetent valves and 10 of 11 segments with competent valves were further decellularized using detergents and DNAse. DC resulted in significant decrease in host DNA compared with controls. DC scaffolds, however, retained major extracellular matrix proteins and mechanical integrity. RC resulted in successful repopulation of the lumen and valves of the scaffold with endothelial and smooth muscle cells. Valve mechanical parameters were similar to the native tissue even after DC. Eight of 10 veins with competent valves remained competent even after DC and RC, whereas the two incompetent valves remained incompetent even after DC and RC. The valve closure time to reflux pressure of the tissue-engineered veins was <0.5 second. Conclusions Tissue-engineered veins with valves provide a valid template for future preclinical studies and eventual clinical applications. This technique may enable replacement of diseased incompetent or damaged deep veins to treat axial reflux and thus reduce ambulatory venous hypertension. Copyright © 2015 by the Society for Vascular Surgery. Published by Elsevier Inc.
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| 5. |
- Sumitran-Holgersson, S, et al.
(författare)
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Human natural antibodies cytotoxic to pig embryonic brain cells recognize novel non-Galalpha1,3Gal-based xenoantigens
- 1999
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 159:2, s. 61-347
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Tidskriftsartikel (refereegranskat)abstract
- Transplantation of porcine embryonic brain cells, including dopaminergic neurons, from ventral mesencephalon (VM) is considered a potential treatment for patients with Parkinson's disease. In the present study, we characterized the distribution among VM cells of the major porcine endothelial xenoantigen, the Galalpha1,3Gal epitope, and evaluated the cytotoxic effect of anti-Galalpha1,3Gal antibody-depleted and nondepleted human AB serum on VM cells. Overall levels of Galalpha1,3Gal-epitope expression was very low on the VM cell population using Bandeiraea simplicifolia IB(4) lectin staining of resuspended VM cells in flow cytometric analyses or staining of SDS-PAGE-separated, solubilized VM cell membrane proteins in Western blot analyses. Lectin-histochemical staining of sections of pig embryonal VM regions with BSA IB(4) lectin showed staining restricted to endothelial cells and microglia. In the presence of complement, both nondepleted and anti-Galalpha1,3Gal antibody-depleted AB sera were shown to be cytotoxic to VM cells as assessed in microcytotoxicity- and flow cytometry-based cytotoxicity assays. Purified IgM and IgG were both cytotoxic in the presence of complement. Three major VM cell membrane antigens of approximately 210, 105, and 50 kDa were reactive with natural IgM antibodies present in pooled human AB sera. Thus, antibody-dependent cytotoxicity may contribute to pig to human brain cell xenorejection, necessitating donor tissue modifications prior to a more widespread utilization of neural tissue xenografting.
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- Ström, Valter, et al.
(författare)
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A novel and rapid method for quantification of magnetic nanoparticle-cell interactions using a desktop susceptometer
- 2004
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Ingår i: Nanotechnology. - : IOP Publishing. - 0957-4484 .- 1361-6528. ; 15:5, s. 457-466
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Tidskriftsartikel (refereegranskat)abstract
- Activated endothelial cells (EC) are attractive prime targets for specific drug delivery using drug-carrying magnetic nanoparticles. In order to accomplish EC targeting, the interaction between magnetic particles and resting as well as activated endothelial cells must be characterized and quantified, because it will influence particle biodistribution, circulation half-time, and targeting efficacy. Here, we have quantified in vitro the interaction (adhesion/phagocytosis) between human endothelial cells and magnetite (Fe3O4) particles carrying different surface coatings with varying degrees of hydrophilicity and surface charge. Almost no adhesion was observed (about 1% or less) for three out of five particle types carrying plain dextran, carboxyl-substituted poly(ethylene glycol) and silica C18 coatings. In contrast, carboxyl-functionalized dextran and poly(ethylene glycol)-coated particles adhered or were phagocytosed to a considerable degree (58 and 26%, respectively). These clear and accurate results were obtained by measuring the magnetic response, i.e. magnetic susceptibility, from different fractions of the cell cultures as a means of determining the concentration of magnetic particles. Visible light and electron microscopy confirmed the magnetic quantification. To meet the need for a rapid yet sensitive instrument, we have developed a desktop magnetic susceptometer especially adapted for liquid samples or particles in a suspension. Despite its very high sensitivity, it is easy to operate and requires but a few seconds for a measurement. We also describe the construction and operation of this instrument.
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| 27. |
- Sumitran-Holgersson, S, et al.
(författare)
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Activated porcine embryonic brain endothelial cells induce a proliferative human T-lymphocyte response
- 2003
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Ingår i: Cell Transplantation. - : SAGE Publications. - 1555-3892 .- 0963-6897. ; 12:6, s. 637-646
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Tidskriftsartikel (refereegranskat)abstract
- Transplantation of allogeneic embryonic neural tissue is a potential treatment for patients with Parkinson's and Huntington's diseases. The supply of human donor tissue is limited, and alternatives such as the use of animal (e.g., porcine) donor tissue are currently being evaluated. Before porcine grafts can be used clinically, strategies to prevent neural xenograft rejection must be developed. Knowledge on how human T lymphocytes recognize porcine embryonic neural tissue would facilitate the development of such strategies. To investigate the ability of porcine embryonic brain microvascular endothelial cells (PBMEC) to stimulate human T-cell proliferation, PBMEC were immuno-magnetically isolated and cocultured with purified human CD4 or CD8 single-positive T cells. PBMEC had a cobblestone-like growth pattern and expressed the endothelial cell markers CD31 and CD106. PBMEC stimulated with the supernatant of phytohemagglutinin-activated porcine peripheral blood mononuclear cells or porcine IFN-gamma, but not nonstimulated PBMEC, induced proliferation of both CD8 and CD4 T cells as assessed by [H-3]thymidine incorporation. Flow cytometric analyses showed that the degree of CD8 and CD4 T cell proliferation correlated with the expression levels of class I and 11 major histocompatibility complex (MHC) antigens, respectively. PBMEC expressed a CTLA-4/Fc-reactive molecule, most likely CD86, suggesting that these cells are able to deliver a costimulatory signal to the T cells. Human TNF-alpha, but not human IFN-gamma, induced class I, but not class II, MHC expression on PBMEC. Within a neural graft or the regional lymph nodes, PBMEC might stimulate human T cells via the direct pathway, and should therefore be removed from the donor tissue prior to transplantation.
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| 29. |
- Sumitran-Holgersson, S, et al.
(författare)
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Porcine embryonic brain cell cytotoxicity mediated by human natural killer cells
- 1999
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Ingår i: Cell Transplantation. - : SAGE Publications. - 0963-6897 .- 1555-3892. ; 8:6, s. 10-601
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Tidskriftsartikel (refereegranskat)abstract
- Intracerebral transplantation of porcine embryonic dopamine-producing neurons has been suggested as a method to treat patients with Parkinson's disease. Even though the brain is an immunologically privileged site, neuronal xenografts are usually rejected within a few weeks. T cells are important for this process, but the exact cellular events leading to rejection are poorly characterized. Brain cells from ventral mesencephalon of 26-27-day-old pig embryos were used as target cells in flow cytometry-assessed cytotoxicity assays using non- and IL-2-activated CD3- CD16+ CD56+ human natural killer (NK) cells as effector cells. The ability of human NK cells to kill pig embryonic brain cells by antibody-dependent cellular cytotoxicity (ADCC) in the presence of nondepleted and anti-Gal alpha1,3Gal antibody-depleted human blood group AB serum (AB serum) was evaluated using the same assay. Both nondepleted and anti-Gal alpha1,3Gal antibody-depleted AB serum could mediate ADCC of pig embryonic VM cells when human NK cells were used as effector cells. Nonactivated NK cells did not show any direct cytotoxic effect on freshly isolated VM cells, whereas IL-2-activated NK cells killed approximately 50% of the VM cells at an effector-to-target ratio of 50:1 in a 4-h cytotoxicity assay. Activation of VM cells by TNF-alpha did not change their sensitivity to human NK cell cytotoxicity. Human NK cells may thus contribute to a cellular rejection of pig neuronal xenografts by ADCC, or following IL-2 activation, by a direct cytotoxic effect.
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| 31. |
- Tait, Brian D, et al.
(författare)
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Consensus Guidelines on the Testing and Clinical Management Issues Associated With HLA and Non-HLA Antibodies in Transplantation.
- 2013
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Ingår i: Transplantation. - 1534-6080. ; 95:1, s. 19-47
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The introduction of solid-phase immunoassay (SPI) technology for the detection and characterization of human leukocyte antigen (HLA) antibodies in transplantation while providing greater sensitivity than was obtainable by complement-dependent lymphocytotoxicity (CDC) assays has resulted in a new paradigm with respect to the interpretation of donor-specific antibodies (DSA). Although the SPI assay performed on the Luminex instrument (hereafter referred to as the Luminex assay), in particular, has permitted the detection of antibodies not detectable by CDC, the clinical significance of these antibodies is incompletely understood. Nevertheless, the detection of these antibodies has led to changes in the clinical management of sensitized patients. In addition, SPI testing raises technical issues that require resolution and careful consideration when interpreting antibody results. METHODS: With this background, The Transplantation Society convened a group of laboratory and clinical experts in the field of transplantation to prepare a consensus report and make recommendations on the use of this new technology based on both published evidence and expert opinion. Three working groups were formed to address (a) the technical issues with respect to the use of this technology, (b) the interpretation of pretransplantation antibody testing in the context of various clinical settings and organ transplant types (kidney, heart, lung, liver, pancreas, intestinal, and islet cells), and (c) the application of antibody testing in the posttransplantation setting. The three groups were established in November 2011 and convened for a "Consensus Conference on Antibodies in Transplantation" in Rome, Italy, in May 2012. The deliberations of the three groups meeting independently and then together are the bases for this report. RESULTS: A comprehensive list of recommendations was prepared by each group. A summary of the key recommendations follows. Technical Group: (a) SPI must be used for the detection of pretransplantation HLA antibodies in solid organ transplant recipients and, in particular, the use of the single-antigen bead assay to detect antibodies to HLA loci, such as Cw, DQA, DPA, and DPB, which are not readily detected by other methods. (b) The use of SPI for antibody detection should be supplemented with cell-based assays to examine the correlations between the two types of assays and to establish the likelihood of a positive crossmatch (XM). (c) There must be an awareness of the technical factors that can influence the results and their clinical interpretation when using the Luminex bead technology, such as variation in antigen density and the presence of denatured antigen on the beads. Pretransplantation Group: (a) Risk categories should be established based on the antibody and the XM results obtained. (b) DSA detected by CDC and a positive XM should be avoided due to their strong association with antibody-mediated rejection and graft loss. (c) A renal transplantation can be performed in the absence of a prospective XM if single-antigen bead screening for antibodies to all class I and II HLA loci is negative. This decision, however, needs to be taken in agreement with local clinical programs and the relevant regulatory bodies. (d) The presence of DSA HLA antibodies should be avoided in heart and lung transplantation and considered a risk factor for liver, intestinal, and islet cell transplantation. Posttransplantation Group: (a) High-risk patients (i.e., desensitized or DSA positive/XM negative) should be monitored by measurement of DSA and protocol biopsies in the first 3 months after transplantation. (b) Intermediate-risk patients (history of DSA but currently negative) should be monitored for DSA within the first month. If DSA is present, a biopsy should be performed. (c) Low-risk patients (nonsensitized first transplantation) should be screened for DSA at least once 3 to 12 months after transplantation. If DSA is detected, a biopsy should be performed. In all three categories, the recommendations for subsequent treatment are based on the biopsy results. CONCLUSIONS: A comprehensive list of recommendations is provided covering the technical and pretransplantation and posttransplantation monitoring of HLA antibodies in solid organ transplantation. The recommendations are intended to provide state-of-the-art guidance in the use and clinical application of recently developed methods for HLA antibody detection when used in conjunction with traditional methods.
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| 35. |
- Albler, F. J., et al.
(författare)
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A comparison of two methods of recovering cobalt from a deep eutectic solvent: Implications for battery recycling
- 2017
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Ingår i: Journal of Cleaner Production. - : Elsevier BV. - 0959-6526. ; 167, s. 806-814
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Tidskriftsartikel (refereegranskat)abstract
- Progress towards a sustainable industrial process for the recycling of unwanted batteries using a deep eutectic solvent is presented. The effect of lactate anions on the recovery of metals from chloride media by extraction by a lipophilic chloride ionic liquid has been investigated with using solvent extraction experiments with a special emphasis on the behaviour of cobalt and nickel. A new solvent extraction system for the recovery of both cobalt and nickel from acidic (lactic acid) media is presented. The relative impacts of the new extraction system and an aliquat system on both workplace air and the wider environment are compared. The new system was found to pose a smallet threat to both workers and the environment.
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| 36. |
- Alheim, M., et al.
(författare)
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The outcome of the endothelial precursor cell crossmatch test in lymphocyte crossmatch positive and negative patients evaluated for living donor kidney transplantation
- 2013
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Ingår i: Human Immunology. - : Elsevier BV. - 0198-8859 .- 1879-1166. ; 74:11, s. 1437-1444
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Tidskriftsartikel (refereegranskat)abstract
- The presence of human leukocyte antigen (HLA) and non-HLA antibodies (Abs) in kidney transplant recipients is associated with graft rejections. This study reports the results of an endothelial precursor cell crossmatch (EPCXM) test for detection of non-HLA Abs and its correlation to lymphocyte crossmatch (LXM) test results, the degree and type of sensitization, and transplantation (Tx) outcome in patients evaluated for living donor (LD) kidney transplantation (Krx). Patients were tested before any pre-transplantation (pre-Tx) treatment and at Tx. Pre-Tx treatments included B cell depletion and Ab removal. Patient records were reviewed for assessment of renal graft function, results of biopsies, and identification of complications affecting the graft. Pre-Tx sera from 32% of the LD patients had IgG and/or IgM-binding donor EPCs. Twenty-five percent of the patients were EPCXM IgM+. Of the patients with negative LXM tests, 25% had EPC Abs mainly of IgM class not reactive with HLA. There was no difference in rejection frequency or serum creatinine levels between the EPCXM+ and EPCXM- groups. The pre-Tx EPCXM+ group had significantly more patients with delayed graft function. Prospective studies with appropriate control groups are needed to establish whether pre-treatments aiming at removing anti-endothelial cell antibodies, as detected by the EPCXM pre-Tx, have a beneficial effect on short-term and long-term graft survival. (C) 2013 American Society for Histocompatibility and Immunogenetics.
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| 39. |
- Bentmar Holgersson, Magdalena, et al.
(författare)
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Androgen receptor polymorphism dependent variation in prostate specific antigen concentrations of European men.
- 2014
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Ingår i: Cancer Epidemiology Biomarkers & Prevention. - 1538-7755. ; 23:10, s. 2048-2056
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Tidskriftsartikel (refereegranskat)abstract
- Background Androgens acting via the androgen receptor (AR) stimulate production of prostate specific antigen (PSA), which is a clinical marker of prostate cancer (PCa). Since genetic variants in the AR may have a significant impact on the risk of being diagnosed with PCa, the aim was to investigate if AR-variants were associated with the risk of having PSA above clinically used cut-off thresholds of 3 or 4 ng/mL in men without PCa. Methods Men without PCa history (n=1744) were selected from the European Male Ageing Study (EMAS) cohort of 40-80 year old men from 8 different European centers. Using linear and logistic regression models, with age and center as covariates, we investigated whether AR-variants (CAG repeat-length and/or SNP genotype) were associated with having serum PSA concentrations above 3 or 4 ng/mL, which often are set as cut-off concentrations for further investigation of PCa. Results Carriers of the SNP rs1204038 A-allele (16% of the men) were more likely to have PSA>3 and 4 ng/mL (OR; 95%CI 1.65; 1.13-2.40 and 1.87; 1.18-2.96, respectively) than G-allele carriers. They also had shorter CAG-repeats (median 20 vs. 23, p<0.0005), but CAG repeat length per se did not affect the PSA concentrations. Conclusion The A-allele of the SNP rs1204038 gives a 65% higher risk of having PSA above 3 ng/mL than the G-allele in men without PCa, and thereby an increased risk of being referred for further examination on suspicion of PCa. Impact Serum PSA as a clinical marker could be improved by adjustment for AR-genotype.
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| 42. |
- Brevig, T, et al.
(författare)
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Xenotransplantation for CNS repair : immunological barriers and strategies to overcome them
- 2000
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Ingår i: Trends in Neurosciences. - 0166-2236. ; 23:8, s. 44-337
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Tidskriftsartikel (refereegranskat)abstract
- Neural transplantation holds promise for focal CNS repair. Owing to the shortage of human donor material, which is derived from aborted embryos, and ethical concerns over its use, animal donor tissue is now considered an appropriate alternative. In the USA, individuals suffering from Parkinson's disease, Huntington's disease, focal epilepsy or stroke have already received neural grafts from pig embryos. However, in animal models, neural tissue transplanted between species is usually promptly rejected, even when implanted in the brain. Some of the immunological mechanisms that underlie neural xenograft rejection have recently been elucidated, but others remain to be determined and controlled before individuals with neurological disorders can benefit from xenotransplantation.
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