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Roider E.,Ludwig Maximilians University of Munich | Jellbauer S.,Ludwig Maximilians University of Munich | Kohn B.,Ludwig Maximilians University of Munich | Berchtold C.,Ludwig Maximilians University of Munich | And 5 more authors.
Cancer Immunology, Immunotherapy | Year: 2011

We have developed a new vaccination strategy by using the Salmonella type III secretion system (T3SS) to translocate heterologous antigens into the cytosol of host cells. This leads to an efficient antigen-specific CD8 T cell induction. Recently, we have demonstrated the use of Salmonella's T3SS for the immunoprophylaxis of a solid tumor. The murine fibrosarcoma WEHI 164 was transfected with the DNA sequence encoding the MHC class I-peptide p60 217-225 from Listeria monocytogenes. In the present study, we used this tumor model to investigate the potential of vaccination with recombinant Salmonella in a therapeutic setting. BALB/c mice were subcutaneously challenged with WEHI-p60 cells. Simultaneously or 4 days later, these mice received either an orogastric or intravenous immunization with Salmonella translocating p60. Interestingly, 71-80% of the intravenously and 50-52% of the orogastrically immunized mice showed a complete tumor regression after 14 days. In addition, the distribution of tetramer-positive p60217-225-specific CD8 T cell subpopulations in blood and tumor tissue was analyzed. Co-staining with CD62L and CD127 revealed that the frequencies of p60217-225-specific effector and effector memory CD8 T cells in blood and in fibrosarcoma tissue were related to the kinetics of tumor regression. In summary, our study demonstrates that therapeutic vaccination with Salmonella leads to efficient induction of tumor-invading effector CD8 T cells that may result in significant tumor regression. © 2010 Springer-Verlag. Source


Lingner T.,Institute for Microbiology | Kataya A.R.A.,University of Stavanger | Reumann S.,University of Stavanger
Plant Signaling and Behavior | Year: 2012

We recently developed the first algorithms specifically for plants to predict proteins carrying peroxisome targeting signals type 1 (PTS1) from genome sequences.1 As validated experimentally, the prediction methods are able to correctly predict unknown peroxisomal Arabidopsis proteins and to infer novel PTS1 tripeptides. The high prediction performance is primarily determined by the large number and sequence diversity of the underlying positive example sequences, which mainly derived from EST databases. However, a few constructs remained cytosolic in experimental validation studies, indicating sequencing errors in some ESTs. To identify erroneous sequences, we validated subcellular targeting of additional positive example sequences in the present study. Moreover, we analyzed the distribution of prediction scores separately for each orthologous group of PTS1 proteins, which generally resembled normal distributions with group-specific mean values. The cytosolic sequences commonly represented outliers of low prediction scores and were located at the very tail of a fitted normal distribution. Three statistical methods for identifying outliers were compared in terms of sensitivity and specificity. Their combined application allows elimination of erroneous ESTs from positive example data sets. This new post-validation method will further improve the prediction accuracy of both PTS1 and PTS2 protein prediction models for plants, fungi, and mammals. © 2012 Landes Bioscience. Source


Bosilkovski M.,Ss. Cyril and Methodius University of Skopje | Zezoski M.,Medical Center Prilep | Siskova D.,Medical Center Shtip | Miskova S.,Medical Center Veles | And 4 more authors.
Clinical Rheumatology | Year: 2016

The aim of the study was to determine the main demographic, epidemiological, clinical characteristics, and outcome in patients with various types of brucellar monoarticular involvement. Retrospectively, we analyzed medical histories of 331 patients with brucellar monoarticular involvement who were treated at the infectious diseases departments in Prilep, Shtip, and Veles, Republic of Macedonia, during the period 1990–2012. Their data were compared accordingly to the affected joint (sacroiliac, hip, knee, ankle, wrist, and shoulder).Patients with shoulder arthritis were significantly the oldest (mean ± standard deviation [SD] 46.0 ± 14.5 years) whereas sacroiliitis and hip arthritis were present predominantly in younger patients (mean ± SD 28.7 ± 14.1 and 28.3 ± 18.3 years, respectively) (p = 0.014). Shoulder arthritis duration was significantly the longest (mean ± SD 24.5 ± 12.4 days), and wrist arthritis duration was significantly the shortest (mean ± SD 4.1 ± 2.5 days) (p < 0.001), before establishing the diagnosis of brucellosis. With appropriate treatment, the need for restitution of the joint impairment was significantly longer when sacroiliitis and hip arthritis were present (mean ± SD 32.8 ± 23.0 and 24.6 ± 12.5 days, respectively) (p < 0.001). The relapses were noted in 14.5, 14, 16.5, 5.5, 6, and 5.5 % of the patients with sacroiliitis, hip-, shoulder-, knee-, ankle-. and wrist arthritis, respectively. In endemic areas, brucellosis should be included in the differential diagnostic consideration in patients with monoarticular involvement. Knee-, ankle-, and wrist arthritis seem to be more benign and with appropriate treatment result in short duration and satisfactory outcome. On the other hand, the involvement of sacroiliac, hip-, and shoulder joint deserves more serious approach due to longer arthritis duration and higher frequency of relapses. © 2016 International League of Associations for Rheumatology (ILAR) Source


Konig S.,Helmholtz Center for Infection Research | Probst-Kepper M.,Institute for Microbiology | Reinl T.,Helmholtz Center for Infection Research | Jeron A.,Helmholtz Center for Infection Research | And 3 more authors.
PLoS ONE | Year: 2012

Regulatory T cells (Tregs) are essential for controlling peripheral tolerance by the active suppression of various immune cells including conventional T effector cells (Teffs). Downstream of the T cell receptor (TCR), more than 500 protein kinases encoded by the human genome have to be considered in signaling cascades regulating the activation of Tregs and Teffs, respectively. Following TCR engagement, Tregs posses a number of unique attributes, such as constitutive expression of Foxp3, hyporesponsiveness and poor cytokine production. Furthermore, recent studies showed that altered regulation of protein kinases is important for Treg function. These data indicate that signaling pathways in Tregs are distinctly organized and alterations at the level of protein kinases contribute to the unique Treg phenotype. However, kinase-based signaling networks in Tregs are poorly understood and necessitate further systematic characterization. In this study, we analyzed the differential expression of kinases in Tregs and Teffs by using a kinase-selective proteome strategy. In total, we revealed quantitative information on 185 kinases expressed in the human CD4+ T cell subsets. The majority of kinases was equally abundant in both T cell subsets, but 11 kinases were differentially expressed in Tregs. Most strikingly, Tregs showed an altered expression of cell cycle kinases including CDK6. Quantitative proteomics generates first comparative insight into the kinase complements of the CD4+ Teff and Treg subset. Treg-specific expression pattern of 11 protein kinases substantiate the current opinion that TCR-mediated signaling cascades are altered in Tregs and further suggests that Tregs exhibit significant specificities in cell-cycle control and progression. © 2012 König et al. Source


Probst-Kepper M.,Institute for Microbiology | Probst-Kepper M.,Helmholtz Center for Infection Research | Balling R.,University of Luxembourg | Buer J.,University of Duisburg - Essen
Current Molecular Medicine | Year: 2010

FOXP3 is essential for the development and function of regulatory CD4+CD25hi T (Treg) cells. However, recent evidence suggests that FOXP3 alone is not sufficient to completely explain the regulatory phenotype of these key players in autoimmunity and inflammation: after being activated, conventional human CD4+ T cells transiently up-regulate FOXP3 without acquiring a regulatory function. Researchers have recently found that glycoprotein A repetitions predominantly (GARP, or LRRC32) is a Treg-specific receptor that binds latent TGF-β and dominantly controls FOXP3 and the regulatory phenotype via a positive feedback loop. This finding provides a missing link in our molecular understanding of FOXP3 in Treg cells. This viewpoint focuses on GARP as safeguard of FOXP3 and the regulatory phenotype. © 2010 Bentham Science Publishers Ltd. Source

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