1,234 research outputs found
Polyomavirus BK-specific cellular immune response in Kidney transplant recipients
No full textPolyomavirus BK is an emerging pathogen in KT recipients. New potent
immunosuppressive drugs promote reactivation and replication of BKV and progression
towards PVAN. PVAN occurs in up to 10% of the KT recipients with a graft loss in up to
80% of the cases. New potent immunosuppressive drugs, as MMF) and FK506 are risk factors
for developing PVAN. As no proven antiviral drugs are available, the only therapy of choice
is the reduction of immunosuppressiva in order to regain BKV-replication control (H. H.
Hirsch, M. Dickenmann, S. Binggeli, J. Steiger, Schweiz Med Forum 2004; 4:538–541).
BKV-specific cellular and humoral immune response is not well characterized. Recent
findings have shown that BKV-seropositive patients prior to transplantation are not protected
from BKV-replication. In contrast, BKV-specific cellular immune response correlates with
the diagnosis of PVAN (P. Comoli, S. Binggeli, F. Ginevri, H. H. Hirsch, Transplant
Infectious Disease Jun 2006; 8(2):86-94, Review).
The aim of this study was to investigate the interplay of BKV-specific immune response
and BKV-replication in blood samples of KT recipients. We examined the BKV-specific
immune response by ELISpot assay in KT. PBMC of KT recipients were stimulated with
BKV LT-antigen and BKV-VP1 peptide libraries. The BKV-specific immune response was
measured by the detection of IFN-γ by ELISpot assay. From the results of a pilot study with
eight patients we were able to deduce that the dynamics of viral-replication rather than the
viral load correlates with a protective immune response (S. Binggeli, A. Egli, M.
Dickenmann, I. Binet, J. Steiger, H. H. Hirsch, American Journal of Transplantation, Sep
2006; 6(9):2218-9).
To corroborate this previous observation the BKV-specific cellular immunity in 42 KT
recipients and 10 HB were tested. The KT patients were divided into two groups: patient
group 1 with an increasing or stable viral load (inc/hi)1 and patient group 2 with a decreasing
viral load or after resolved PVAN (dec)2. Indeed patients in group 2 showed a significantly
higher immune response upon stimulation with BKV-LT and BKV-VP1 than patients in
group 1 (P=0.003, P=0.001, respectively, Wilcoxon, two-sided). Detailed analysis revealed a
cut-off of >69 SFU/Mio PBMC for BKV LT-antigen, but not for BKV VP1, with
significantly more KT patients from group 2 (dec) than from group 1 (inc/hi). This cut-off has
to be validated in a prospective study and also analyzed whether such a cut-off can be used for
immunosuppressive reduction guidance.
BKV-specific cell expansion was tested in a short-term culture in the presence of either
BKV-LT or -VP1. After 9-day culture, PBMC were restimulated with BKV-LT or -VP1 and
the responses were then compared with responses to direct stimulation (without prior
cultivation). BKV-LT and -VP1 specific cellular immune responses were significantly higher
after 9-day cultivation than after direct stimulation (P=0.002, P=0.003, respectively,
Wilcoxon, two sided).
Due to high sequence homology between JCV and BKV, JCV-LT and -VP1 overlapping
peptide pools were used to test PBMC-cross recognition. JCV-LT and -VP1 responses were
significantly lower than BKV-mediated response (P=0.008, P<0.001, respectively, Wilcoxon,
two-sided). Comparison of JCV- and BKV-specific responses after 9-day culture revealed that
the BKV-VP1 response was significantly higher than the JCV-VP1 (P=0.016, Wilcoxon, two
sided), but no significant difference was observed for LT-antigen (S. Binggeli, A. Egli, S.
Schaub, I. Binet, M. Mayr, J. Steiger, H. H. Hirsch, American Journal of Transplantation, Mar
2007; 7:1-9).
Agnoprotein, a late viral protein, is highly expressed upon infection. We investigated
whether agnoprotein is able to induce a BKV-specific immune response and whether it may
serve as a diagnostic marker. Immunostaining revealed that agnoprotein was highly expressed
in the cytoplasm of infected cells and was only seen in combination with BKV-LT which is
located in the nucleus. Interestingly, BKV-agnoprotein specific cellular and humoral immune
responses were scarcely detected in HB or KT recipients. There are only few published
studies concerning BKV-agnoprotein, and further investigations are necessary to fully
understand the function of agnoprotein during infection. (D. Leuenberger, P. A. Andresen, R.
Gosert, S. Binggeli, E. H. Ström, S. Bodaghi, C Hanssen Rinaldo, H. H. Hirsch, Clinical and
Vaccine Immunology, Aug 2007; 14(8): 959-968).
As no antiviral treatment is available for BKV, the only therapy is the reduction of
immunosuppressive drugs in order to regain immunological control over BKV-replication and
PVAN. However reduction of immunosuppressants upon PVAN diagnosis bears the risk of
rejection or inflammatory response to BKV. It is difficult to distinguish between these two
outcomes because specific markers are yet lacking. Therefore, it is pivotal to record the
clinico-pathological course of the KT patient in order to correctly diagnose the problem as the
therapies are completely different. Measuring the BKV-specific cellular immune response
may support and complement other markers, such as PCR analysis and biopsies, to better
distinguish between rejection and BKV-specific immune response. (S. Schaub, M. Mayr, A.
Egli, S. Binggeli, B. Descoeudres, J. Steiger, M. J. Mihatsch, H. H. Hirsch, Nephrology
Dialysis Transplantation, Aug 2007; 22(8): 2386-90).
Finding the optimal immunosuppressive drug level is crucial for preventing rejection
(under-immunosuppressed) and viral replication (over-immunosuppressed). Our current study
showed a cut-off level of 6.65 ng/ml FK506 drug level in blood, dividing those KT patients
with and without BKV-replication control (ROC-curve: AUC=0.897, sensitivity=78%,
specificity=86%). If this cut-off is validated by a well designed prospective study, it may
serve as a guideline to administrate the optimal drug level. (S. Binggeli, 2007, current results).
BKV-specific epitopes have received considerable attention in the last five years. We
started with the epitope mapping in a kidney patient with the most common HLA-type: HLAA*
01, HLA-B*08. First screening of BKV-LT revealed ten 15aa long peptides with
immunogenic potential. Three of these ten peptides were further investigated for crossrecognition
with the homologous JCV-peptides. Even though response to the three JCVpeptides
was lower, cellular immune response could be clearly detected. It needs further
investigation to find more BKV-specific epitopes and also to test the ability of CD8+ T-cells
to kill BKV-antigen presenting cells. (S. Binggeli, 2007, current results)
Tracking Virus-Specific CD4+ T Cells during and after Acute Hepatitis C Virus Infection
No full textBackground. CD4+ T cell help is critical in maintaining antiviral immune responses and such help has been shown to be sustained in acute resolving hepatitis C. In contrast, in evolving chronic hepatitis C CD4+ T cell helper responses appear to be absent or short-lived, using functional assays. Methodology/Prencipal Findings. Here we used a novel HLA-DR1 tetramer containing a highly targeted CD4+ T cell epitope from the hepatitis C virus non-structural protein 4 to track number and phenotype of hepatitis C virus specific CD4+ T cells in a cohort of seven HLA-DR1 positive patients with acute hepatitis C in comparison to patients with chronic or resolved hepatitis C. We observed peptide-specific T cells in all seven patients with acute hepatitis C regardless of outcome at frequencies up to 0.65% of CD4+ T cells. Among patients who transiently controlled virus replication we observed loss of function, and/or physical deletion of tetramer+ CD4+ T cells before viral recrudescence. In some patients with chronic hepatitis C very low numbers of tetramer+ cells were detectable in peripheral blood, compared to robust responses detected in spontaneous resolvers. Importantly we did not observe escape mutations in this key CD4+ T cell epitope in patients with evolving chronic hepatitis C. Conclusions/Significance. During acute hepatitis C a CD4+ T cell response against this epitope is readily induced in most, if not all, HLA-DR1 + patients. This antiviral T cell population becomes functionally impaired or is deleted early in the course of disease in those where viremia persists
Modulation of the CD8+-T-cell response by CD4+ CD25+ regulatory T cells in patients with Hepatitis B virus infection
No full textCD4+ CD25+ regulatory T cells have been shown to maintain peripheral tolerance against self and foreign
antigens. In this study we analyzed the effect of circulating CD4+ CD25+ T cells on CD8+-T-cell responses of
patients with chronic and resolved hepatitis B virus (HBV) infection. We demonstrated that circulating CD4+
CD25+ T cells modulate the function and expansion of HBV-specific CD8+ cells ex vivo in all patients,
regardless of whether they have chronic or resolved HBV infection. The possible role of CD4+ CD25+ T cells
in the pathogenesis of chronic HBV infection is not supported by these data. However, these results might have
implications for optimizing future immunotherapeutic approaches to HBV treatment
Analysis of the conform process: a specific form of aluminium extrusion.
No full textSince the Conform process was patented 30 years ago, there have only been approximately 200 machines sold worldwide. Given that Conform competes economically with conventional extrusion and is also reported to be a more energy
efficient process, it is surprising that the use of Conform is not more widespread in today's increasingly environmentally conscious and high-production focussed world. One explanation for this is likely to be due to the fact that there is still limited knowledge of the thermo-mechanical behaviour of the workpiece during extrusion.
Furthermore, for the aluminium industry, there are still issues remaining regarding the production of flash and the quality of the extrudate in terms of mechanical properties. This study provides the reader with the findings of the research and experimental work undertaken by the author, his co-workers and fellow specialists, in the field of aluminium extrusion including Conform. The experimental work includes both laboratory experiments performed with a direct extrusion press and an experimental machine set up to replicate the Conform process. The experimental work is also simulated using finite element modelling techniques. The results from these analyses are then validated by comparing industrial and experimental data. The finite element analyses are enhanced by using parallel processing technology and user sub-routines. The author proposes new models to allow for the study of the different sub-processes in Conform. These include the coining of the feedstock, formation of the upset zone, extrusion of the flash, the filling-up of the expansion chamber / feeder plate and the extrusion of the extrudate. The author also investigates methods which predict microstructure and surface cracks in the extrudate. The author suggests innovative techniques to improve the efficiency of finite element analysis in metal forming. Finally the author recommends procedures for the study of structural integrity and the optimisation of the tooling used in Conform
Data assimilation-based surface temperature reconstructions over the last two millennia over Antarctica
No full textThis dataset contains data assimilation-based temperature and δ18O reconstructions in 10 Antarctic regions over the last two millennia, presented in :
Klein, F., Abram, N. J., Curran, M. A. J., Goosse, H., Goursaud, S., Masson-Delmotte, V., Moy, A., Neukom, R., Orsi, A., Sjolte, J., Steiger, N., Stenni, B., and Werner, M.: Assessing the robustness of Antarctic temperature reconstructions over the past two millennia using pseudoproxy and data assimilation experiments, Clim. Past Discuss., https://doi.org/10.5194/cp-2018-90, in review, 2018.
We use a new database of stable oxygen isotopes in ice cores compiled in the framework of Antarctica2k (Stenni et al., 2017) to constrain model ensembles derived from two simulations: one performed using ECHAM5-MPI-OM that covers the period 800-1999 CE with a horizontal resolution of 3.75° by 3.75° (Sjolte et al., 2018), and the other performed with ECHAM5-wiso, spanning 1871-2011 CE at 1.125° spatial resolution (Steiger et al., 2017). This latter simulation is available here.
Four netCDF files are available:
d18O_DA_ECHAM5-MPI-OM_1-2015.nc: data assimilation-based δ18O reconstructions using the model ensemble derived from ECHAM5-MPI-OM
ts_DA_ECHAM5-MPI-OM_1-2015.nc: data assimilation-based surface temperature reconstructions using the model ensemble derived from ECHAM5-MPI-OM
d18O_DA_ECHAM5-wiso_1-2015.nc: data assimilation-based δ18O reconstructions using the model ensemble derived from ECHAM5-wiso
ts_DA_ECHAM5-wiso_1-2015.nc: data assimilation-based surface temperature reconstructions using the model ensemble derived from ECHAM5-wiso
The variables included in the NetCDF files are:
region: integers from 1 to 10 corresponding to the ID of the ten reconstructions targets, that were defined in Stenni et al. (2017):
1: East Antarctic Plateau
2: Wilkes Land Coast
3: Weddell Sea Coast
4: Antarctic Peninsula
5: West Antarctic Ice Sheet
6: Victoria Land Coast-Ross Sea
7: Dronning Maud Land Coast
8: West Antarctica
9: East Antarctica
10: Antarctica
time: integers from 1 to 2015, corresponding to the years CE covered by the reconstructions
DA_ts (or DA_d18O): data assimilation-based reconstructed surface temperature (or δ18O). The values are annual means and are given in anomalies computed over full period. The units are degrees celsius (or permil).
DA_ts_std (or DA_d18O_std): Weighted standard deviation of the particles used for reconstructing temperature (or δ18O). The units are degrees celsius (or permil).
For a detailed description of the experimental design, please see the associated publication (Klein et al., 2018). Don't hesitate to contact François Klein for more information.
References
Klein, F., Abram, N. J., Curran, M. A. J., Goosse, H., Goursaud, S., Masson-Delmotte, V., Moy, A., Neukom, R., Orsi, A., Sjolte, J., Steiger, N., Stenni, B., and Werner, M.: Assessing the robustness of Antarctic temperature reconstructions over the past two millennia using pseudoproxy and data assimilation experiments, Clim. Past Discuss., https://doi.org/10.5194/cp-2018-90, in review, 2018.
Sjolte, J., Sturm, C., Adolphi, F., Vinther, B. M., Werner, M., Lohmann, G., and Muscheler, R.: Solar and volcanic forcing of North Atlantic climate inferred from a process-based reconstruction, Climate of the Past, 14, 1179–1194, https://doi.org/10.5194/cp-14-1179-2018, 2018.
Steiger, N. J., Steig, E. J., Dee, S. G., Roe, G. H., and Hakim, G. J.: Climate reconstruction using data assimilation of water isotope ratios from ice cores, Journal of Geophysical Research: Atmospheres, 122, 1545–1568, https://doi.org/10.1002/2016JD026011, 2017.
Stenni, B., Curran, M. A. J., Abram, N. J., Orsi, A., Goursaud, S., Masson-Delmotte, V., Neukom, R., Goosse, H., Divine, D., van Ommen, T., Steig, E. J., Dixon, D. A., Thomas, E. R., Bertler, N. A. N., Isaksson, E., Ekaykin, A., Werner, M., and Frezzotti, M.: Antarctic climate variability on regional and continental scales over the last 2000 years, Climate of the Past, 13, 1609–1634, https://doi.org/10.5194/cp-13-1609-2017, 2017.</p
Atomic force microscopy study of tabular AgBr microcrystals (T-grains)
No full textThe new method of atomic force microscopy has been applied to tabular AgBr microcrystals (T-grains). AgBr T-grain ensembles of different densities are imaged with high contrast and high lateral resolution. The grain surfaces appear to be very flat over large areas. On the top surfaces of single T-grains, well-developed growth hills are revealed. Heights and diameters of individual T-grains and growth hills are determined. The capabilities of atomic force microscopy are discussed in relation to the carbon replica method and scanning electron microscopy
1.Jg., 7.-12.H. (1794) (2)
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Albrecht von Haller, als Dichter. (521)
Anmerkungen und Zusätze zu Coxe's Reisen. (539)
Anmerkungen und Zusätze zu Coxe's Reisen. (569)
Anonymi aliqua gesta de morte Domini Lupoldi Ducis Austrie et de guerra Dominorum Friburgensium contra Bernenses. Ao 1386-1389. (609)
Die Nymphe des Mains, und der Wandrer. (637)
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Nachricht von einem bisher ganz unbekannten Eydgenößischen Chronickschreiber. (650)
Le Tombeau de Gessner. (654)
Das Bistum Basel. Genauer als bisher, doch nicht nach seinem neuesten Zustande, beschrieben. I. J. 1791. (659)
Briefwechsel zweyer Landpfarrer über Wielands Briefe der Verstorbenen. (Bald nach der ersten Erscheinung derselben.) (689)
Ueber Herrn Meiners Nachrichten, die Stadt St. Gallen betreffend. Meiners, C.: Briefe über die Schweiz. T.1-4. Berlin: Spener 1788-90.: Rezension (710)
Unsere Bestimmung. (714)
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Ueber einige Erziehungs- und Bildungsanstalten in Zürich. (737)
Lindor und Cora. (748)
Verzeichniß von topographischen Kupferstichen und Holzschnitten des Canton Luzern. (754)
Reise durch die Waat. (773)
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Verzeichnis von Topographischen Kupferstichen und Holzschnitten den Canton Uri betreffend. (862)
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Peter Steiger. (Geb.1459. St.1499.) (893)
Johann Steiger Freyherr zu Oron, Roll, Mont le Vieux und Mont le Grand Herr zu Biere, Beignin, Rosty, Cuarney, Sepey, Molan, Alaman, Münsingen und Wichtrach. (895)
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Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes
No full textWe thank the comparative experimental pathology team for discussions, and A. Selmeier, L. Dajka, O. Seelbach, P. Meyer, T. Schmidt, J. Eichinger and T. Stauber for technical assistance as well as M. Reichert for vector constructs. The work was supported by the German Cancer Consortium Joint Funding Program, the Helmholtz Gemeinschaft (PCCC Consortium), the German Research Foundation (SFB1243; A13/A14) and the European Research Council (ERC CoG number 648521).Mueller, S., Engleitner, T., Maresch, R., Zukowska, M., Lange, S., Kaltenbacher, T., Konukiewitz, B., Öllinger, R., Zwiebel, M., Strong, A., Yen, H.-Y., Banerjee, R., Louzada, S., Fu, B., Seidler, B., Götzfried, J., Schuck, K., Hassan, Z., Arbeiter, A., Schönhuber, N., Klein, S., Veltkamp, C., Friedrich, M., Rad, L., Barenboim, M., Ziegenhain, C., Hess, J., Dovey, O.M., Eser, S., Parekh, S., Constantino-Casas, F., De La Rosa, J., Sierra, M.I., Fraga, M., Mayerle, J., Klöppel, G., Cadiñanos, J., Liu, P., Vassiliou, G., Weichert, W., Steiger, K., Enard, W., Schmid, R.M., Yang, F., Unger, K., Schneider, G., Varela, I., Bradley, A., Saur, D., Rad, R
Characterizing determinants of BK Polyomavirus-specific immune response
No full textBK polyomavirus (BKPyV) is one of now 13 human polyomavirus (HPyV) species detected in humans. BKPyV is only known to infect humans and seroprevalence rates of more than 90% have been reported in adult populations around the world. Following primary infection, BKPyV persists in the renourinary tract without causing any disease as evidenced by urinary shedding in 5% - 10% of healthy immunocompetent blood donors.
In immunocompromised persons, however, BKPyV can cause significant diseases whereby uncontrolled high-level replication may lead to organ invasive pathologies in kidneys, bladder, lungs, vasculature, and the central nervous system. The most consistently found diseases are BKPyV-associated hemorrhagic cystitis (BKPyVHC) in 5%-20% allogeneic hematopoietic stem cells transplant patients, and BKPyV-associated nephropathy (BKPyVAN) in 1%-15% of kidney transplant patients. BKPyVHC is highly symptomatic with pain, anemic bleeding, and increased mortality. BKPyVAN is asymptomatic except for progressive renal failure and premature return to dialysis. Both entities are characterized by high-level viral replication i.e. with urine BKPyV loads of 8-10 log10 Geq/mL, plasma BKPyV loads often above 4 log10 Geq/mL, and an allogeneic constellation between the virus-infected host cell and the available T-cell effectors. Despite these similarities, the clinical manifestations are strikingly different suggesting relevant, but experimentally undefined differences in pathogenesis. Thus, BKPyVHC typically occurs within 4 weeks after allogeneic HSCT and is confined to the bladder, and typically without kidney involvement. By contrast, BKPyVAN is diagnosed around 3-6 months after kidney transplantation and confined to the kidney allograft without causing cystitis. Although high-level BKPyV replication should be formally amenable to antiviral drug treatment, no effective and BKPyV-specific antiviral therapy is currently available. Therefore, a better understanding of the immune alteration in both diseases has been deemed essential to identify patients at risk and to develop prophylactic, preemptive and therapeutic strategies.
The currently recommended strategy for BKPyVAN is to screen kidney transplant patients for BKPyV replication and to promptly reduce immunosuppressive therapy in those with significant replication to facilitate mounting of BKPyV-specific T cell responses and thereby preventing progression to disease. This manoeuver has been linked to expanding BKPyV-specific T cell responses in the peripheral blood of kidney transplant patients. However, this approach may place patients at risk for acute rejection episodes that predispose equally well to premature kidney transplant failure. Although the clinical feasibility of reducing immunosuppression and curtailing BKPyV replication has been shown to be effective in prospective cohort studies for many, but not all of kidney transplant patients, this approach has not been possible in allogeneic HSCT patients because of concurrent or imminent graft-versus host disease. Thus, there are significant gaps in the current understanding of the BKPyV– host interaction in the normal host and in the allogeneic setting, which need to be investigated for a more effective and safer management of these significant viral complications.
In this thesis, the interaction of BKPyV and the immune response has been approached from two different angles. In the first project, potential mechanisms of BKPyV immune evasion were studied. Here, we focused on a small accessory protein called agnoprotein encoded as a leader protein in the late viral early region (LVGR). Although HPyV genomes overall show a very similar genome organization, agnoproteins are only found in the genomes of BKPyV and JCPyV that have a kidney tropisms, but not in any of the other 11 presumably non-renotropic HPyVs. We hypothesized that agnoprotein could play a role in immune evasion by downregulating HLA expression. The effects of agnoprotein were studied on HLA class I and II expression in vitro by flow cytometry following transfection of primary human renal tubular epithelial cells, which are the viral target of BKPyV-associated nephropathy. In addition, transfected human UTA-6 cells were studied as well as UTA-6 cells bearing a tetracycline-regulated agnoprotein. As control, the effects were compared with the ICP47 protein of Herpes simplex virus-1, which has been previously reported to effectively down-regulate HLA class I. Although both viral proteins share some similarities at the protein level, our results showed that BKPyV agnoprotein did not down-regulate HLA class I or class II molecules. Also, there was not inhibitory effect on the increase of HLA-class I or class-II surface expression following exposure to interferon-. By contrast, ICP47 reduced HLA class I surface expression, but not class II. We also evaluated effects of agnoprotein on virus epitope-specific T-cell killing by 51Chromium release assay, however no interference could be observed. We concluded that agnoprotein did not contribute to these types of HLA-dependent immune evasion processes. However, further investigations are needed to understand if agnoprotein could contribute to viral immune escape by other mechanisms.
In the second project, we aimed at better characterizing BKPyV-specific CD8 T cell immunity targeting epitopes encoded in the early viral gene region (EVGR). Selected coding sequences of the BKPyV EVGR were submitted to two web-based computer algorithms (SYFPEITHI, IEDB) in order to predict immunodominant 9mer epitopes presented by 14 frequent HLA-class I molecules. For an experimental confirmation, 97 different 9mer epitopes were chemically synthesized and tested in 42 healthy individuals. A total of 39 epitopes could be confirmed by interferon- ELISpot assay in at least 30% of healthy individuals. Interestingly, most of the 9mer epitopes appeared to cluster in short amino acid stretches, and some 9mer could be presented by more than one HLA class I allele as expected for immunodominant domains. HLA-specific presentation was demonstrated by 9mer- MHC-I streptamers for 21/39 (54%) epitopes. The 9mer dependent T-cell killing by 51Chromium release assay and the CD107a surface detection indicated that the 9mer epitopes could be recognized by cytotoxic T-cells. Moving to a clinically relevant situation, 13 9mer epitopes could be validated in 19 kidney transplant patients protected from, or recovering from, BKPyV viremia. The results suggest that, pending further corroboration in larger patient populations, novel 9mer epitopes can be identified, which are associated with CD8 T cell control of BKPyV replication. Thus the identified immunodominant 9mer T-cell epitopes could be further developed for clinical assays to better predict the risk and the recovery of BKPyV diseases, help guiding immunosuppression reduction, and to develop specific adoptive T-cell therapy or vaccine responses to prevent or treat BKPyV-associated disease
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