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  • 1
    Keywords: APOPTOSIS ; CELLS ; ENDOTHELIAL-CELLS ; tumor ; TUMOR-CELLS ; CELL ; Germany ; IN-VIVO ; VIVO ; SYSTEM ; liver ; MICE ; MECHANISM ; INDUCTION ; ANTIGEN ; ANTIGENS ; DENDRITIC CELLS ; T cell ; T cells ; T-CELLS ; TOLERANCE ; BONE-MARROW ; CANCER-CELLS ; NATURAL-KILLER-CELLS ; FRAGMENTS ; FAILURE ; ADAPTIVE IMMUNITY ; TUMOR CELLS ; ELIMINATION ; IMMUNE ESCAPE ; IMMUNE-SYSTEM ; ESCAPE ; CYTOKINE PRODUCTION ; TUMOR-CELL ; KUPFFER CELLS ; in vivo ; FRAGMENT ; CD8(+) T cell ; COLON-CARCINOMA CELLS ; liver sinusoidal endothelial cells ; NKT CELLS ; PERFORIN/GRANZYME PATHWAY ; sinusoidal endothelial cells
    Abstract: Development of tumor-specific T cell tolerance contributes to the failure of the immune system to eliminate tumor cells. Here we report that hematogenous dissemination of tumor cells followed by their elimination and local removal of apoptotic tumor cells in the liver leads to subsequent development of T cell tolerance towards antigens associated with apoptotic tumor cells. We provide evidence that liver sinusoidal. endothelial cells (LSEC) remove apoptotic cell fragments generated by induction of tumor cell apoptosis through hepatic NK1.1(+) cells. Antigen associated with apoptotic cell material is processed and cross-presented by LSEC to CD8(+) T cells, leading to induction of CD8(+) T cell tolerance. Adoptive transfer of LSEC isolated from mice challenged previously with tumor cells promotes development of CD8(+) T cell tolerance towards tumor-associated antigen in vivo. Our results indicate that hematogenous dissemination of tumor cells, followed by hepatic tumor cell elimination and local cross-presentation of apoptotic tumor cells by LSEC and subsequent CD8(+) T cell tolerance induction, represents a novel mechanism operative in tumor immune escape
    Type of Publication: Journal article published
    PubMed ID: 17039564
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  • 2
    Keywords: CANCER ; EXPRESSION ; CELL ; Germany ; IN-VIVO ; THERAPY ; VIVO ; SYSTEM ; TOOL ; liver ; GENE ; GENE-EXPRESSION ; GENES ; PROTEIN ; MICE ; MACROPHAGES ; INDUCTION ; tumour ; BIOLOGY ; culture ; MOUSE ; gene expression ; VECTORS ; PROMOTER ; REGION ; VACCINES ; REGIONS ; DELIVERY ; Jun ; CARRIERS ; GREEN FLUORESCENT PROTEIN ; LUCIFERASE ; CYTOSINE DEAMINASE ; RE ; THERAPIES ; REPORTER GENE ; CARRIER ; HISTOLOGY ; in vivo ; E ; TOOLS ; spleen ; microbiology ; ENGLAND ; host ; FLUORESCENT PROTEIN ; FLUORESCENT ; PLASMIDS ; bacterial ; ARABAD PROMOTER ; tumour therapy
    Abstract: We have used Salmonella enterica serovar Typhimurium (S. typhimurium) which are able to colonize tumours besides spleen and liver. Bacteria were equipped with constructs encoding green fluorescent protein or luciferase as reporters under control of the promoter P-BAD that is inducible with L-arabinose. Reporter genes could be induced in culture but also when the bacteria resided within the mouse macrophages J774A.1. More important, strong expression of reporters by the bacteria could be detected in mice after administration of L-arabinose. This was especially pronounced in bacteria colonizing tumours. Histology demonstrated that the bacteria had accumulated in and close to necrotic areas of tumours. Bacterial gene induction was observed in both regions. P-BAD is tightly controlled also in vivo because gene E of bacteriophage Phi X174 could be introduced as inducible suicide gene. The possibility to deliberately induce genes in bacterial carriers within the host should render them extremely powerful tools for tumour therapy
    Type of Publication: Journal article published
    PubMed ID: 17298393
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  • 3
    Keywords: APOPTOSIS ; CELLS ; SURVIVAL ; Germany ; PATHWAY ; DEATH ; DISEASE ; GENE ; PROTEIN ; METABOLISM ; MICE ; ALZHEIMERS-DISEASE ; ACID ; CELL-SURVIVAL ; MOUSE ; CELL-DEATH ; MUTATION ; MUTATIONS ; XENOPUS ; DIET ; AMYLOID-BETA-PEPTIDE ; neurodegeneration ; 2-METHYL-3-HYDROXYBUTYRYL-COA DEHYDROGENASE-DEFICIENCY ; ERAB ; HSD10 ; organic aciduria
    Abstract: Deficiency of the mitochondrial enzyme 2-methyl-3-hydroxybutyryl-CoA dehydrogenase involved in isoleucine metabolism causes an organic aciduria with atypical neurodegenerative course. The disease-causing gene is HSD17B10 and encodes 17 beta-hydroxysteroid dehydrogenase type 10 (HSD10), a protein also implicated in the pathogenesis of Alzheimer's disease. Here we show that clinical symptoms in patients are not correlated with residual enzymatic activity of mutated HSD10. Loss-of-function and rescue experiments in Xenopus embryos and cells derived from conditional Hsd17b10(-/-) mice demonstrate that a property of HSD10 independent of its enzymatic activity is essential for structural and functional integrity of mitochondria. impairment of this function in neural cells causes apoptotic cell death whilst the enzymatic activity of HSD10 is not required for cell survival. This finding indicates that the symptoms in patients with mutations in the HSD17B10 gene are unrelated to accumulation of toxic metabolites in the isoleucine pathway and, rather, related to defects in general mitochondrial function. Therefore alternative therapeutic approaches to an isoleucine-restricted diet are required
    Type of Publication: Journal article published
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  • 4
    Keywords: PEPTIDE ; CELLS ; Germany ; MOLECULES ; TIME ; ACTIVATION ; COMPLEX ; COMPLEXES ; IMPACT ; DOMAIN ; ANTIGEN ; T cell ; T-CELL ; BINDING ; ASSOCIATION ; FIELD ; MOLECULE ; IDENTIFICATION ; NUMBER ; antigen presentation ; HLA-DM ; RECRUITMENT ; LOADING COMPLEX ; ENDOPLASMIC-RETICULUM ; OXIDOREDUCTASE ERP57 ; PEPTIDE-LOADING COMPLEX ; RE ; development ; PROTEIN DISULFIDE-ISOMERASE ; CALRETICULIN ; 1,25D(3)-MARRS ; ERp57
    Abstract: Antigen presentation by MHC class I molecules is necessary for CD8 T-cell activation. Optimal peptide loading onto MHC class I molecules occurs mainly in the peptide-loading complex in the endoplasmic reticulum. The identification of a covalent association between the thiol oxidoreductase ERp57 and tapasin, and its impact on the loading complex, are important recent developments in this field of research. In the absence of ERp57, the recruitment of MHC class I molecules into this complex by tapasin is greatly impaired both in the number of molecules and in their interaction time, suggesting a key structural role for the ERp57-tapasin association in the peptide-loading complex. The role of ERp57 as a thiol oxidoreductase in the peptide-loading complex remains, however, controversial and further research regarding this subject is required
    Type of Publication: Journal article published
    PubMed ID: 17150345
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