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  • 1
    Keywords: CANCER ; CELLS ; EXPRESSION ; Germany ; IN-VIVO ; ADHESION MOLECULES ; MICE ; COMPLEX ; COMPLEXES ; tumour ; ANTIGEN ; CONTRAST ; DENDRITIC CELLS ; T-CELL ; T-CELLS ; FREQUENCY ; MOLECULE ; bone marrow ; BONE-MARROW ; virus ; LINE ; ADHESION ; NAIVE ; ADHESION MOLECULE ; EFFECTOR ; adoptive immunotherapy ; FEATURES ; RE ; CLASS-II ; PROTECTIVE IMMUNITY ; memory T cells ; PERSISTENCE ; CD8(+) T-cell memory ; GAMMA-IRRADIATION ; LYMPHOCYTES-T ; tumour dormancy
    Abstract: LacZ (Gal)-reactive immune cells were transferred into athymic nu/nu mice inoculated with Gal-expressing syngeneic tumour cells (ESbL-Gal) in order to study tumour-protective T-cell memory. This transfer prevented tumour outgrowth in recipients and resulted in the persistence of a high frequency of Gal-specific CD8(+) T cells in the bone marrow and spleen. In contrast, such Ag-specific memory CD8(+) T cells were not detectable by peptide-major histocompatibility complex (MHC) multimer staining in animals that had not previously received an antigenic challenge. Even though CD44(hi) memory T cells from the bone marrow showed a significantly higher turnover rate, as judged by bromodeoxyuridine (BrdU) incorporation, than respective cells from spleen or lymph nodes, as well as in comparison to CD44(lo) naive T cells, these findings suggest that tumour-associated antigen (TAA) from residual dormant tumour cells are implicated in maintaining high frequencies of long-term surviving Gal-specific memory CD8(+) T cells. Memory T cells could be recruited to the peritoneal cavity by tumour vaccination of immunoprotected nu/nu mice and exhibited ex vivo antitumour reactivity. Long-term immune memory and tumour protection could be maintained over four successive transfers between tumour-inoculated recipients, which involved periodic antigenic restimulation in vivo prior to reisolating the cells for adoptive transfer. Using a cell line (ESbL-Gal-BM) that was established from dormant tumour cells isolated from the bone marrow of immunoprotected animals, it could be demonstrated that the tumour cells had up-regulated the expression of MHC class I molecules and down-regulated the expression of several adhesion molecules during the in vivo passage. Our results suggest that the bone marrow microenvironment has special features that are of importance for the maintenance of tumour dormancy and immunological T-cell memory, and that a low level of persisting antigen favours the maintenance of Ag-specific memory T cells over irrelevant memory T cells
    Type of Publication: Journal article published
    PubMed ID: 15946250
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  • 2
    Keywords: PEPTIDE ; APOPTOSIS ; CANCER ; CELLS ; tumor ; TUMOR-CELLS ; CELL ; Germany ; human ; IN-VIVO ; VIVO ; PROTEIN ; PROTEINS ; TISSUE ; TUMORS ; MICE ; PATIENT ; LIGAND ; REDUCTION ; INDUCTION ; TISSUES ; ANTIGEN ; ANTIGENS ; DENDRITIC CELLS ; SKIN ; T cell ; T cells ; T-CELL ; T-CELLS ; bone marrow ; BONE-MARROW ; BREAST ; breast cancer ; BREAST-CANCER ; IMMUNE-RESPONSES ; MEMORY ; NOD/Scid mice ; RECOGNITION ; GLYCOPROTEIN ; PEPTIDES ; PHENOTYPE ; CANCER-PATIENTS ; CD8(+) ; P-SELECTIN ; REJECTION ; NAIVE ; CANCER PATIENTS ; TUMOR CELLS ; EFFECTOR ; CLUSTER ; SCID MICE ; TUMOR-ASSOCIATED ANTIGENS ; AUTOLOGOUS TUMOR ; breast tumors ; homing ; IMMUNOLOGICAL MEMORY ; INFILTRATION ; PROGRAM ; SELECTIN LIGANDS ; SUBSET
    Abstract: Bone marrow of breast cancer patients was found to contain CD8(+) T cells specific for peptides derived from breast cancer-associated proteins MUC1 and Her-2/neu. Most of these cells had a central or effector memory phenotype (CD45RA(-)CD62L(+) or CD45RA(-)CD62L(-), respectively). To test their in vivo function, we separated bone marrow-derived CD45RA(+) naive or CD45RA(-)CD45RO(+) memory T cells, stimulated them with autologous dendritic cells pulsed with tumor lysate, and transferred them into NOD/SCID mice bearing autologous breast tumors and normal skin transplants. CD45RA(-) memory but not CD45RA(+) naive T cells infiltrated autologous tumor but not skin tissues after the transfer. These tumor-infiltrating cells had a central or effector memory phenotype and produced perforin. Many of them expressed the beta-selectin glycoprotein ligand 1 and were found around beta-selectin(+) tumor endothelium. Tumor infiltration included cluster formation in tumor tissue by memory T cells with cotransferred dendritic cells. It was associated with the induction of tumor cell apoptosis and significant: tumor reduction. We thus demonstrate selective homing of memory T cells to human tumors and suggest that tumor rejection is based on the recognition of tumor-associated antigens on tumor cells and dendritic cells by autologous specifically activated central and effector memory T cells
    Type of Publication: Journal article published
    PubMed ID: 15232613
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  • 3
    Keywords: CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; human ; DISEASE ; GENE ; PROTEIN ; TISSUE ; LINES ; ACTIVATION ; DNA ; MECHANISM ; TISSUES ; mechanisms ; TOLERANCE ; CELL-LINES ; EXPRESSION ANALYSIS ; CELL-LINE ; LINE ; DNA methylation ; EPITHELIAL-CELLS ; SELECTION ; GERM-LINE ; cell lines ; expression profiling ; METHYLATION ; REGULATOR ; HYPOMETHYLATION ; AUTOIMMUNITY ; thymus ; HUMAN CANCER ; DEFICIENT MICE ; AIRE ; AUTOIMMUNE REGULATOR ; THYMIC EPITHELIAL-CELLS ; PROMISCUOUS GENE-EXPRESSION ; LOSSES ; lymph node ; LYMPH-NODE ; DEFICIENT ; DEFECT ; autoimmune disease
    Abstract: Defects in the autoimmune regulator (AIRE) gene cause the monogenic autoimmune disease autoimmune polyendocrinopathy syndrome type I (APS-1), which is characterized by a loss of self-tolerance to multiple organs. In concordance with its role in immune tolerance, AIRE is strongly expressed in medullary thymic epithelial cells (mTECs). Data on mechanisms controlling AIRE activation and the expression of this gene in other tissues are fragmentary and controversial. We report here AIRE mRNA expression profiling of a large set of normal human tissues and cells, tumor specimen and methylation deficient cell lines. On this broad data basis we found that AIRE mRNA expression is confined to mTECs in thymus and to lymph node tissue and that DNA hypomethylation contributes to transcriptional control of this gene. (c) 2006 Elsevier B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16876259
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  • 4
    Keywords: CELLS ; proliferation ; BLOOD ; Germany ; human ; DIFFERENTIATION ; ANTIGEN ; T-CELL ; T-CELLS ; MEMORY ; LYMPHOCYTES ; CD8(+) ; NAIVE ; PERIPHERAL-BLOOD ; SUBSETS ; EFFECTOR ; RE ; memory T cells
    Type of Publication: Journal article published
    PubMed ID: 16034079
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  • 5
    Keywords: CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; human ; MODEL ; MODELS ; DISEASE ; DISEASES ; RISK ; PROTEIN ; transcription ; DIFFERENTIATION ; MICE ; INDUCTION ; ANTIGEN ; T cell ; T-CELL ; TOLERANCE ; SUSCEPTIBILITY ; SUSCEPTIBILITY LOCUS ; TARGET ; PATTERNS ; HUMANS ; EPITHELIAL-CELLS ; REGULATOR ; insulin ; MELLITUS ; PROGRAM ; RE ; IDDM2 LOCUS ; INSULIN EXPRESSION ; T-CELL TOLERANCE ; PROMISCUOUS GENE-EXPRESSION ; LEVEL ; HAPLOTYPE ; LOCUS ; RISK-FACTOR ; immunology ; autoimmune disease ; animal ; promiscuous gene expression ; central tolerance ; AIRE GENE ; CLASS-III ALLELES ; type 1 diabetes mellitus
    Abstract: Induction of T cell tolerance in the thymus (central tolerance) is essential for preventing organ-specific autoimmunity. This apparent paradox is in part explained by promiscuous expression of numerous tissue-restricted self-antigens (TRA) in medullary thymic epithelial cells (mTEC), which is highly conserved between mice and man. In animal models, the threshold of central tolerance towards such TRA is surprisingly sensitive towards minor shifts in antigen expression levels and this might also be the case in humans. To precisely assess the inter-individual variability of TRA expression in man, we determined the level of transcription of several auto-antigens in purified human mTEC and subsets thereof by quantitative RT-PCR. We detected two expression patterns: first, high variability (〉 20-fold) correlated with autoimmune regulator (Aire) expression and mTEC differentiation, and secondly, non-correlated low variability. importantly, our approach revealed a significantly higher Aire-correlated insulin transcription in mTEC of carriers of the protective insulin-dependent diabetes mellitus locus 2 haplotype compared to the non-protective haplotype. The considerable, yet selective variability in thymic expression levels of target auto-antigen expression might constitute a hitherto underestimated risk factor for the susceptibility of autoimmune diseases in man
    Type of Publication: Journal article published
    PubMed ID: 17323415
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