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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: RECEPTOR ; APOPTOSIS ; CELLS ; EXPRESSION ; IN-VITRO ; IONIZING-RADIATION ; CELL ; IN-VIVO ; MODEL ; VITRO ; VIVO ; SYSTEM ; DEATH ; MICE ; NEUROBLASTOMA-CELLS ; NITRIC-OXIDE SYNTHASE ; NITRIC-OXIDE ; IFN-GAMMA ; DONOR ; INDUCTION ; tumour ; DOWN-REGULATION ; INDUCED APOPTOSIS ; UP-REGULATION ; SIGNALING PATHWAYS ; KAPPA-B ; FACTOR-I ; TNF-ALPHA ; CD95 ; INCREASE ; FAS ; SYNTHASE ; MEDIATED APOPTOSIS ; death receptor ; function ; CANDIDATE ; nitric oxide ; in vivo ; immunology
    Abstract: Both the function and regulation of Fas expression in tumours is poorly understood. Our laboratory has reported that cultured, low Fas-expressing tumours undergo massive, yet reversible, up-regulation of cell surface Fas expression when injected into mice. The present study was aimed at determining what causes this enhanced Fas expression and whether the newly expressed Fas functions as a death receptor. Newly expressed Fas is indeed capable of inducing apoptosis. Based on our observation that Fas induction is reduced when tumour cells are injected into immune-deficient mice, we propose that Fas up-regulation in vivo involves the host's immune system. Accordingly, Fas up-regulation occurs in vitro when low Fas-expressing tumour cells are cocultured with lymphoid cells. Furthermore ascitic fluid extracted from tumour-bearing mice trigger Fas up-regulation in low Fas expressing tumours. This last finding suggests that a soluble factor(s) mediates induction of Fas expression. The best candidate for this soluble factor is nitric oxide (NO) based on the following observations: the factor in the ascites is unstable; Fas expression is induced to a lesser degree after injection into inducible NO synthase (NOS)-deficient (iNOS(-/-)) mice when compared to control mice; similarly, coculture with iNOS(-/-) splenocytes induces Fas less effectively than coculture with control splenocytes; and finally, the NO donor SNAP induces considerable Fas up-regulation in tumours in vitro. Our model is that host lymphoid cells in response to a tumour increase NO synthesis, which in turn causes enhanced Fas expression in the tumour
    Type of Publication: Journal article published
    PubMed ID: 17343612
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  • 3
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    Immunology 152 (4), 536-544 
    Abstract: Immunotherapies have been traditionally applied in malignant melanoma, which represent one of the most immunogenic tumours. Recently, immune checkpoint modulation has shown high therapeutic efficacy and may provide long-term survival in a significant proportion of affected patients. T cells are the major players in tumour rejection and recognize tumour cells predominantly in an MHC-dependent way. The immunopeptidome comprises the peptide repertoire presented by MHC class I and II molecules on the surface of the body's cells including tumour cells. To understand characteristics of suitable rejection antigens as well as respective effective T-cell responses, determination of the immunopeptidome is of utmost importance. Suitable rejection antigens need to be further characterized and validated not only to systematically improve current therapeutic approaches, but also to develop individualized treatment options. In this review, we report on current tools to explore the immunopeptidome in human melanoma and discuss current understanding and future developments to specifically detect and select those antigens that may be most relevant and promising for effective tumour rejection.
    Type of Publication: Journal article published
    PubMed ID: 28755382
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  • 4
    Abstract: Colorectal cancer is considered a non-immunogenic malignany. One strategy to augment the immunogenicity of such tumours is represented by the expression of costimulatory molecules by gene transfer. Using transfected variants of the human colorectal cancer cell line SW480 we tested various costimulatory molecules (CD80, CD86, CD54) and a class II major histocompatibility complex (MHC) allele (HLA-DR3) alone or in combination on their ability to support primary T-lymphocyte activation in vitro. Expression of CD80 or CD86 similarly as the combination of both was not sufficient to induce proliferation of human allogeneic T cells. Expression of CD54 together with CD80 strongly augmented the costimulatory function of CD80, as observed in the presence of a CD3 monoclonal antibody (mAb), but did not lead directly to a T-cell response against modified tumour cells. Importantly, SW480 cells coexpressing CD54, CD80 and the HLA-DR3 allele effectively promoted T-lymphocyte proliferation. Moreover, the use of such CD54+/CD80+/HLA-DR3+ SW480 variants for repetitive stimulations resulted in the generation of T-cell lines predominantly composed of CD8+ T cells exhibiting class I MHC restricted cytolytic activity towards untransfected SW480 tumour cells. This demonstrates that the generation of immunogenic tumour cell variants, i.e. for the use as cellular vaccines, requires multiple genetic alterations in the case of non-immunogenic human tumours cells, such as colorectal cancer cells.
    Type of Publication: Journal article published
    PubMed ID: 9640250
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  • 5
    Keywords: CELLS ; EXPRESSION ; proliferation ; BLOOD ; IN-VIVO ; ACTIVATION ; RESPONSES ; INDUCTION ; ANTIGEN ; CONTRAST ; T-CELL ; T-CELLS ; TOLERANCE ; SUPPRESSION ; GLYCOPROTEIN ; HUMANS ; NUMBER ; SWEDEN ; PHENOTYPE ; INTERFERON ; CHILDREN ; HEALTHY ; cord blood ; myelin oligodendrocyte glycoprotein ; THYMOCYTES ; AUTOIMMUNITY ; thymus ; ADULT ; ADULTS ; RE ; EFFECTOR FUNCTION ; CYTOKINE PRODUCTION ; ABILITY ; CD25(+) regulatory T cells
    Abstract: Activation of self-reactive T cells in healthy adults is prevented by the presence of autoantigen-specific CD4(+)CD25(+) regulatory T cells (CD25(+) T-reg). To explore the functional development of autoantigen-reactive CD25(+) T-reg in humans we investigated if thymic CD25(+) T-reg from children aged 2 months to 11 years and cord blood CD25(+) T-reg are able to suppress proliferation and cytokine production induced by specific antigens. While CD4(+)CD25(-) thymocytes proliferated in response to myelin oligodendrocyte glycoprotein (MOG), tetanus toxoid and beta-lactoglobulin, suppression of proliferation was not detected after the addition of thymic CD25(+) T-reg. However, CD25(+) T-reg inhibited interferon (IFN)-gamma production induced by MOG, which indicates that MOG-reactive CD25(+) T-reg are present in the thymus. In contrast, cord blood CD25(+) T-reg suppressed both proliferation and cytokine production induced by MOG. Both cord blood and thymic CD25(+) T-reg expressed FOXP3 mRNA. However, FOXP3 expression was lower in cord blood than in thymic CD25(+) T cells. Further characterization of cord blood CD25(+) T cells revealed that FOXP3 was highly expressed by CD25(+)CD45RA(+) cells while CD25(+)CD45RA(-) cells contained twofold less FOXP3, which may explain the lower expression level of FOXP3 in cord blood CD25(+) T cells compared to thymic CD25(+) T cells. In conclusion, our data demonstrate that low numbers of MOG-reactive functional CD25(+) T-reg are present in normal thymus, but that the suppressive ability of the cells is broader in cord blood. This suggests that the CD25(+) T-reg may be further matured in the periphery after being exported from the thymus
    Type of Publication: Journal article published
    PubMed ID: 16011520
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  • 6
    Keywords: APOPTOSIS ; EXPRESSION ; IN-VITRO ; INHIBITOR ; IN-VIVO ; INHIBITION ; VITRO ; PROTEIN ; RNA ; ACCUMULATION ; MICE ; NF-KAPPA-B ; MESSENGER-RNA ; MOLECULAR-BIOLOGY ; BONE-MARROW ; MOUSE ; STAGE ; COX-2 ; protein expression ; inflammation ; INHIBITORS ; INFILTRATION ; PRODUCTS ; DEPENDENCE ; MICE LACKING ; MATRIX-METALLOPROTEINASE-9 ; MMP-9 ; USA ; BONE ; cyclooxygenase ; PROSTAGLANDIN E-2 ; immunology ; MAST-CELLS ; peritoneal inflammation ; EARLY VASCULAR-PERMEABILITY ; MARROW ; neutrophil ; Genetic ; ZYMOSAN-INDUCED PERITONITIS ; GENE DISRUPTION ; matrix metalloproteinase-9 ; prostaglandin D-2 ; ZYMOSAN PERITONITIS
    Abstract: P〉Matrix metalloproteinase-9 (MMP-9)/gelatinase B plays an important role in neutrophil infiltration during inflammation and cyclooxygenases (COX-1 and COX-2) and their products are important regulators of inflammation. Recently, we reported that a genetic lack of MMP-9 impairs neutrophil infiltration during early zymosan-induced peritonitis but at later stages (〉 24 hr) neutrophils persist in the peritoneal cavity. Here we show that this is the result of impaired apoptosis of MMP-9(-/-)-derived leucocytes. As enhanced COX-1 expression was reported in MMP-9(-/-) mice, we evaluated the hypothesis that altered COX expression induced the above phenomenon as COX-dependent prostaglandins can act either anti-apoptotically (PGE(2)) or pro-apoptotically (PGD(2)). The current data demonstrate that messenger RNA and protein expression of both COX isoforms and their activities are increased in MMP-9(-/-) mice during late peritonitis. Application of selective COX inhibitors revealed enhanced COX-1-dependent PGE(2) production and impaired COX-2-dependent PGD(2) synthesis in MMP-9(-/-) mice. Most importantly, inhibition of COX-1 abolished prolonged neutrophil accumulation in the peritoneal cavity of MMP-9(-/-) mice and increased apoptosis of inflammatory leucocytes. Similarly, weaker apoptosis of MMP-9(-/-) bone marrow neutrophils treated in vitro with zymosan was reversed by COX-1 inhibition. In conclusion, enhanced COX-1 expression is responsible for persistent neutrophil presence in the peritoneum of MMP-9(-/-) mice because of increased synthesis of anti-apoptotic PGE(2). In non-transgenic mice, however, inflammatory leucocytes die apoptotically in the late stages of peritonitis as a result of COX-2-dependent PGD(2) activity. Overall, we show a dependence of COX expression on the presence of MMP-9
    Type of Publication: Journal article published
    PubMed ID: 19175797
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  • 7
    Keywords: albumin, ALBUMINURIA, AUTOANTIBODIES, AUTOIMMUNITY, CELL, CELLS, DNA, DOWN-REGULATION, endothelial c
    Abstract: P〉What are the molecular mechanisms of bacterial infections triggering or modulating lupus nephritis? In nephritic MRLlpr/lpr mice, transient exposure to bacterial cell wall components such as lipopeptide or lipopolysaccharide (LPS) increased splenomegaly, the production of DNA autoantibodies, and serum interleukin (IL)-6, IL-12 and tumour necrosis factor (TNF) levels, and aggravated lupus nephritis. Remarkably, bacterial lipopeptide induced massive albuminuria in nephritic but not in non-nephritic mice. This was associated with down-regulation of renal nephrin mRNA and redistribution from its normal localization at foot processes to the perinuclear podocyte area in nephritic MRLlpr/lpr mice. Bacterial lipopeptide activates Toll-like receptor 2 (TLR2), which we found to be expressed on cultured podocytes and glomerular endothelial cells. TNF and interferon (IFN)-gamma induced TLR2 mRNA and receptor expression in both cell types. Albumin permeability was significantly increased in cultured podocytes and glomerular endothelial cells upon stimulation by bacterial lipopeptide. LPS also induced moderate albuminuria. In summary, bacterial lipopeptide and LPS can aggravate glomerulonephritis but only lipopeptide potently induces severe albuminuria in MRLlpr/lpr mice
    Type of Publication: Journal article published
    PubMed ID: 19175801
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  • 8
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; BLOOD ; CELL ; Germany ; human ; IN-VIVO ; VITRO ; VIVO ; DISEASE ; DISEASES ; POPULATION ; GENE ; PROTEIN ; DIFFERENTIATION ; MICE ; ACTIVATION ; LIGAND ; CUTTING EDGE ; MACROPHAGES ; MARKER ; CONTRAST ; DENDRITIC CELLS ; T-CELLS ; INJECTION ; IMMUNE-RESPONSES ; STIMULATION ; MOUSE ; PATTERNS ; UP-REGULATION ; FUSION ; MARKERS ; SURFACE ; LIGANDS ; innate immunity ; POPULATIONS ; REVEALS ; PERIPHERAL-BLOOD ; MONOCYTE ; COLONY-STIMULATING FACTOR ; FUSION PROTEIN ; regulation ; USA ; LPS ; macrophage ; immunology ; peripheral blood ; MONOCYTES ; STEADY-STATE ; myeloid cells ; myeloid-derived suppressor cells ; SUPPRESSOR-CELLS ; SEPTIC SHOCK ; TREM-1 ; Toll-like receptor ; myeloid ; MURINE SEPSIS ; Toll-like receptor ligands ; TREM-1 ligand
    Abstract: P〉Triggering receptor expressed on myeloid cells 1 (TREM-1) is an activating receptor involved in inflammatory diseases and septic shock. The TREM-1 ligand(s) (TREM-1L) have not yet been identified. In this study, we performed a detailed analysis of the expression of mouse TREM-1 and its ligand(s). Our results demonstrate that TREM-1 is expressed on bone-marrow-derived dendritic cells (BMDC). On bone-marrow-derived macrophages (BMM) its expression is induced in vitro after stimulation by granulocyte-macrophage colony-stimulating factor, interleukin-3 or by myeloid differentiation primary response gene 88 (MyD88)-dependent Toll-like receptor (TLR) ligands. Under steady-state conditions mouse TREM-1 is detectable on a Gr-1(-) F4/80(+) monocyte subpopulation bearing markers of resident monocytes, but not on Gr-1(+) F4/80(+) inflammatory monocytes. During lipopolysaccharide (LPS)-induced endotoxaemia TREM-1 was also up-regulated on inflammatory Gr-1(+) F4/80(+) cells in vivo. In tumour-bearing mice, TREM-1 was up-regulated on Gr-1(+) F4/80(+) monocytes, which phenotypically and functionally resembled mononuclear myeloid-derived suppressor cells. Using a soluble TREM-1 fusion protein, we demonstrate that after intravenous injection of LPS TREM-1L was induced on Gr-1(+) granulocytes and monocytes but not on other cell populations in peripheral blood. This up-regulation on granulocytes was directly mediated by TLR ligands and required the adapter protein MyD88. In contrast to human, mouse platelets expressed TREM-1L neither under steady-state conditions nor after LPS injection in vivo. Our study reveals differential regulation of TREM-1 expression on mouse monocyte subpopulations and improves our understanding of the biological role of TREM-1 during disease
    Type of Publication: Journal article published
    PubMed ID: 19740375
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  • 9
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  • 10
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