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  • APOPTOSIS  (2)
  • 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: 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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