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  • 1
    Keywords: PEPTIDE ; CELLS ; EXPRESSION ; IN-VITRO ; tumor ; TUMOR-CELLS ; BLOOD ; Germany ; IN-VIVO ; VITRO ; POPULATION ; TUMORS ; LINES ; PATIENT ; LIGAND ; RESPONSES ; IFN-GAMMA ; ANTIGEN ; DENDRITIC CELLS ; SKIN ; T-CELL ; T-CELLS ; RECOGNITION ; IDENTIFICATION ; LINE ; MELANOMA ; LYMPHOCYTES ; REGION ; LIGANDS ; EPITOPES ; IMMUNOTHERAPY ; vaccination ; PERIPHERAL-BLOOD ; RE ; MELANOMA-CELLS ; TYROSINASE-RELATED PROTEIN-2 ; dendritic cell ; T cell epitope ; T-CELL EPITOPE ; VACCINIA VIRUS ANKARA ; tumor antigen ; HOST-RANGE SELECTION ; TRP-2
    Abstract: Tyrosinase-related protein-2 (TRP-2) is a known target antigen of spontaneous cytotoxic T cell responses in melanoma patients. Its frequent expression in metastatic tumors suggests that it might be an ideal candidate antigen for T cell-based immunotherapy. To provide knowledge about TRP-2-derived T cell epitopes useful for immunotherapy we applied a "reverse immunology strategy" based on repeated in vitro peptide stimulation of peripheral blood lymphocytes (PBL) from normal donors with predicted HLA-A*01 ligands. This led to the identification of TRP-2(181-190) as the first HLA-A*01-presented TRP-2-derived epitope. T-cell lines specific for peptide TRP-2(181-190) could be established from PBL of 50% of the normal HLA-A*01(+) donors tested. Such T cells responded specifically to autologous dendritic cells transduced virally with TRP-2, as well as to HLA-A*01(+), TRP-2(+) melanoma cells, although tumor cells had to be pretreated with IFN-gamma to become susceptible to T cell recognition. Interestingly, short-term in vitro peptide stimulation of PBL from HLA-A*01(+) melanoma patients showed the presence of TRP-2(181-190)-reactive CD8(+) T cells in some donors, suggesting their in vivo sensitization. Because TRP-2(181-190) overlaps with the known HLA-A*0201-presented epitope TRP-2(180-188), an 11mer peptide encompassing both epitopes might be of specific value for vaccination of a broad population of melanoma patients. (C) 2005 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 15856458
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  • 2
    Keywords: PEPTIDE ; RECEPTOR ; CELLS ; tumor ; TUMOR-CELLS ; BLOOD ; CELL ; Germany ; THERAPY ; POPULATION ; PROTEIN ; LINES ; PATIENT ; DNA ; IFN-GAMMA ; MOTIFS ; DONOR ; ANTIGEN ; DENDRITIC CELLS ; SKIN ; T cells ; T-CELLS ; IDENTIFICATION ; LYMPHOMA ; ASSAY ; LINE ; BETA ; PEPTIDES ; EPITOPE ; EPITOPES ; IMMUNOTHERAPY ; TCR ; TARGETS ; FUTURE ; PERIPHERAL-BLOOD ; TUMOR CELLS ; MONONUCLEAR-CELLS ; TUMOR-ASSOCIATED ANTIGENS ; RE ; cutaneous T-cell lymphoma ; TUMOR-CELL ; UNIT ; PLASMID ; peripheral blood ; peripheral blood mononuclear cells ; LYMPHOPROLIFERATIONS ; MELANOMA ANTIGEN ; reverse immunology
    Abstract: The clonotypic T-cell receptor (TCR) is a potential target antigen for specific immunotherapy of cutaneous T-cell lymphoma (CTCL). We identified T-cell epitopes from the rearranged TCR beta chain of the malignant T-cell population by the "reverse immunology" approach. Peptide-specific T-cell lines were generated against predicted epitopes and tested for the recognition of tumor cells and cells transfected with the full-length DNA coding for TCRV beta chain. Two peptides derived from the clonotypic TCRV beta of a HLA-A2 positive patient could induce peptide-specific T cells from peripheral blood mononuclear cells of healthy donors and the patient as assessed by IFN-gamma ELISpot assay. Furthermore, the reactive CTLs efficiently recognized autologous Sezary tumor cells, as well as HLA-A2 positive 293 cells transfected with recombinant plasmid expressing the corresponding TCRV beta 29 protein. Similar results were obtained in a HLA-A3+ patient for TCRV beta 7-J beta 2.7. In conclusion, our experiments show that the TCR beta chain harbors epitopes suitable as targets for specific vaccination which might be a promising approach for the specific immunotherapy of cutaneous T-cell lymphoma patients. (c) 2006 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 16858680
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  • 3
    Keywords: CELLS ; CELL ; Germany ; THERAPY ; CLASSIFICATION ; DISEASE ; GENE ; PATIENT ; prognosis ; TRANSPLANTATION ; DENDRITIC CELLS ; polymorphism ; POLYMORPHISMS ; PROMOTER ; PCR ; REGION ; PHENOTYPE ; immune response ; IMMUNE-RESPONSE ; PROGNOSTIC VALUE ; CHILDREN ; ATOPY ; molecular ; CHILDHOOD ; THERAPIES ; DEPENDENCE ; secretion ; allergy ; PROMOTER POLYMORPHISM ; methods ; dendritic cell ; GENOTYPE ; NEPHROTIC SYNDROME ; IGE ; PROMOTER REGION ; ENGLAND ; response ; IL-4 ; INTERLEUKIN-13
    Abstract: Background. Steroid-sensitive nephrotic syndrome (NS) of childhood is the most common glomerular disease in children. The type and duration of response to corticosteroid therapy are used for clinical classification, and especially patients with steroid dependence often have a complicated course, requiring intensified immunosuppressive treatment. Its cause is still unknown although a cytokine-mediated course of disease has been implicated. Interleukin 12 (IL-12) is critical in determining the type of immune response. The ability of dendritic cells to secrete bioactive IL-12 is associated with a bi-allelic polymorphism within the promoter region of IL12B, the gene encoding the IL-12 p40 subunit. We hypothesized that this genotype may be involved in steroid-sensitive INS. Methods. Using allele-specific PCR, 79 children with relapsing NS were genotyped for the IL12Bpro polymorphism, and genotype was correlated with clinical phenotype (presence/absence of steroid dependence). Results. Children with the steroid-dependent course are at a significantly higher frequency homozygous for one IL12B allele compared to children without steroid dependence (46.7% and 17.6%, respectively). This genotype has previously been shown to be associated with impaired IL-12 secretion. Conclusion. Polymorphisms in the IL12B promoter region associate with two different clinical courses of NS. The IL12Bpro polymorphism may therefore define molecular subgroups with different prognosis. Further studies are needed to evaluate the prognostic value
    Type of Publication: Journal article published
    PubMed ID: 18632587
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  • 4
    Keywords: CANCER ; CELLS ; EXPRESSION ; AGENTS ; Germany ; SYSTEM ; DISEASE ; DISEASES ; ACTIVATION ; DENDRITIC CELLS ; T-CELLS ; FLOW ; cytokines ; MATURATION ; ASSAY ; STRATEGIES ; IMMUNE-RESPONSE ; IMMUNITY ; AGENT ; SINGLE ; BLOOD MONOCYTES ; CD40 LIGAND ; INTERLEUKIN-12 ; INFLAMMATORY CYTOKINES ; CYTOKINE PRODUCTION ; dendritic cell ; MATURE ; Fc receptor ; INDUCE MATURATION ; intracellular cytokine flow cytometry ; STIMULATORY FACTOR ; TH2 CELLS
    Abstract: Dendritic cells (DCs) are under investigation as immunotherapeutic agents in the treatment of cancer and infectious diseases. One of the important factors in skewing the immune response toward clinically beneficial T(H)1-type immunity is interleukin-12p70. IL-12p70 is synthesized and secreted in response to inflammatory cytokines, bacterial/viral components, and CD40 ligation. This study investigated the production of IL-12 by DCs at the single-cell level using a sensitive intracellular cytokine flow cytometry-based assay system. The authors observed that immature DCs could be stimulated with several compounds to produce IL-12, but that IL-12 production was a feature of a minority of activated DCs. IL-12(+) DCs were characterized as being partially matured (ie, absent or low CD83 expression, with variable expression of CD1a and CD64). Interestingly, activated DCs lacked expression of the CD16 and CD64 Fc gamma R, which may have important implications for exogenous antigen-loading strategies
    Type of Publication: Journal article published
    PubMed ID: 16000948
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  • 5
    Keywords: CANCER ; CELLS ; IN-VITRO ; proliferation ; SURVIVAL ; tumor ; CELL ; CELL-PROLIFERATION ; Germany ; PATHWAY ; VITRO ; FOLLOW-UP ; DISEASE ; GENE ; cell line ; TISSUE ; TUMORS ; LINES ; TIME ; PATIENT ; DNA ; IMPACT ; prognosis ; TISSUES ; SKIN ; CELL-LINES ; polymorphism ; STAGE ; LESIONS ; MUTATION ; skin cancer ; CELL-LINE ; LINE ; MELANOMA ; PCR ; MUTATIONS ; MULTIVARIATE ; MELANOMA PATIENTS ; cell lines ; PROGNOSTIC FACTOR ; BIOPSY ; B-RAF ; BRAF ; SKIN-CANCER ; SINGLE ; PATIENT SURVIVAL ; MELANOMA-CELLS ; overall survival ; MUTATION STATUS ; PROGNOSTIC-FACTOR ; cell proliferation ; N-RAS MUTATIONS ; TUMOR TISSUE ; analysis ; TUMOR-CELL ; multivariate analysis ; UNIT ; cancer research ; CONFORMATION ; SHORT-TERM ; BIOPSIES ; comparison ; German ; outcome ; STRAND ; CLICK
    Abstract: In melanoma, the RAS/RAF/MEK/ERK signalling pathway is an area of great interest, because it regulates tumor cell proliferation and survival. A varying mutation rate has been reported for B-RAF and N-RAS, which has been largely attributed to the differential source of tumor DNA analyzed, e.g., fixed tumor tissues or in vitro propagated melanoma cells. Notably, this variation also interfered with interpreting the impact of these mutations on the clinical course of the disease. Consequently, we investigated the mutational profile of B-RAF and N-RAS in biopsies and corresponding cell lines from metastatic tumor lesions of 109 melanoma patients (AJCC stage III/IV), and its respective impact on survival. 97 tissue biopsies and 105 biopsy-derived cell lines were screened for B-RAF and N-RAS mutations by PCR single strand conformation polymorphism and DNA sequencing. Mutations were correlated with patient survival data obtained within a median follow-up time of 31 months. B-RAF mutations were detected in 55% tissues and 51% cell lines, N-RAS mutations in 23% tissues and 25% cell lines, respectively. There was strong concordance between the mutational status of tissues and corresponding cell lines, showing a differing status for B-RAF in only 5% and N-RAS in only 6%, respectively. Patients with tumors carrying mutated B-RAF showed an impaired median survival (8.0 versus 11.8 months, p = 0.055, tissues; 7.1 versus 9.3 months, p = 0.068, cell lines), whereas patients with N-RAS-mutated tumors presented with a favorable prognosis (median survival 12.5 versus 7.9 months, p = 0.084, tissues; 15.4 versus 6.8 months, p = 0.0008, cell lines), each in comparison with wildtype gene status. Multivariate analysis qualified N-RAS (p = 0.006) but not B-RAF mutation status as an independent prognostic factor of overall survival. Our findings demonstrate that B-RAF and N-RAS mutations are well preserved during short term in vitro propagation and, most importantly, differentially impact the outcome of melanoma patients.
    Type of Publication: Journal article published
    PubMed ID: 17311103
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  • 6
    Abstract: Prostaglandin E(2) (PGE(2)) is an inflammatory mediator often used to increase CCR7 expression in the dendritic cells (DC) used as cancer vaccines and to enhance their responsiveness to lymph-node-associated chemokines. Here, we show that high surface expression of CCR7 on PGE(2)-matured DCs is associated with their suppressed production of the endogenous CCR7-ligand, CCL19, and is reversible by exogenous CCL19. In contrast to the PGE(2)-matured DCs, DCs matured in the presence of TLR-ligands and interferons produce high levels of both CCL19 and CCR7 mRNA/protein, but show selectively-reduced expression of surface CCR7 which is compensated after DC removal from the CCL19-rich maturation environment. In accordance with these findings, PGE(2)-matured DCs show significantly-higher in vitro migratory responsiveness to lymph node-associated chemokines directly after DC generation, but not after additional short-term culture in vitro, nor in vivo in patients injected with (111)In-labelled DCs. The differences in CCL19-producing ability imprinted during DC maturation result in their different abilities to attract CCR7(+) naive T cells. Our data help to explain the impact of PGE(2) on CCR7 expression in maturing DC and demonstrate a novel mechanism of regulatory activity of PGE(2), mediated by the inhibition of DC's ability to attract naive T cells.
    Type of Publication: Journal article published
    PubMed ID: 20498301
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  • 7
    Keywords: CANCER ; EXPRESSION ; GROWTH ; INHIBITOR ; INVASION ; proliferation ; Germany ; PATHWAY ; PATHWAYS ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; DIFFERENTIATION ; LINES ; ACTIVATION ; DNA ; MECHANISM ; tumour ; mechanisms ; BINDING ; CELL-LINES ; DOWN-REGULATION ; gene expression ; MICROARRAY DATA ; microarrays ; NUMBER ; MUTATION ; METASTASIS ; LINE ; MELANOMA ; PCR ; DNA-BINDING ; SIGNALING PATHWAY ; MUTATIONS ; ONCOGENE ; MALIGNANT-MELANOMA ; real-time PCR ; cell lines ; REGULATOR ; INITIATION ; B-RAF ; BRAF ; N-RAS ; TRANSCRIPTS ; MATRIX ; RE ; KINASE PATHWAY ; BRAF MUTATIONS ; MELANOCYTES ; RAS/RAF/MEK/ERK PATHWAY ; transcript
    Abstract: We studied global gene expression in three melanoma cell lines with the most common and potent V600E mutation in the B-RAF gene-four cell lines with a common Q61R mutation in the N-RAS gene and three cell lines with no mutations using human HG-U133A 2.0 micro-arrays with 22 277 transcripts. Data analysis using stringent criteria revealed several upregulated and downregulated genes in cell lines with B-RAF and N-RAS mutations compared with cell lines without mutations. We found 29 genes specifically upregulated and 32 genes downregulated in cell lines with B-RAF mutations, whereas 70 genes were upregulated and 39 downregulated in cell lines with N-RAS mutations; 11 genes showed overlapping upregulation and 45 down-regulation. The micro-array data for nine selected genes were validated by the real-time PCR technique. Expression of a large number of genes, that encode members or regulators of the RAS/RAF/MEK/ERK pathways or are involved in metastasis or invasion, was affected in cell lines with mutations in B-RAF and N-RAS. Upregulated genes in cell lines with mutations included dual-specificity phosphatase 6 (DUSP6), sprouty 2 (SPRY2), v-akt murine thymoma viral oncogene homolog 3 (AKT3) and matrix metalloproteinase 14 (MMP14); downregulated genes included interleukin 18 (IL18), Kruppel-like factor 5 (KLF5) and inhibitor of DNA binding 2 (ID2). Our results, though carried on cell lines, provide a novel insight into the effect of mutations in the B-RAF and N-RAS genes on global gene expression in melanoma and highlight the complexity of mechanisms involved in tumour initiation and maintenance
    Type of Publication: Journal article published
    PubMed ID: 15760917
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  • 8
    Keywords: CANCER ; EXPRESSION ; Germany ; PATHWAY ; PATHWAYS ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; DIFFERENTIATION ; LINES ; ANTIGEN ; CELL-LINES ; DELETION ; gene expression ; microarrays ; NUMBER ; MUTATION ; CELL-LINE ; LINE ; CDKN2A ; MELANOMA ; METASTATIC MELANOMA ; SPORADIC PRIMARY MELANOMAS ; MUTATIONS ; POLYMERASE-CHAIN-REACTION ; MALIGNANT-MELANOMA ; cell lines ; CD24 ; BRAF ; RE ; TUMOR-SUPPRESSOR ; p16(INK4A) ; N-RAS MUTATIONS ; data analysis ; INTERVAL ; LOCUS ; BRAF MUTATIONS ; senescence ; CRITERIA ; downregulation ; A2
    Abstract: We studied differential global gene expression in four melanoma cell lines with three cell lines without homozygous deletion of the CDKN2A locus using HG-U133A microarrays with 22 277 transcripts. None of the cell lines carried mutations in the B-RAF and N-RAS genes. Data analysis using stringent criteria showed specific upregulation of 70 genes and downregulation of 86 genes in cell lines with homozygous deletion of the CDKN2A gene. A comparison with previous expression data showed overlapping of upregulation and downregulation of seven and 23 genes, respectively, in melanoma cell lines with homozygous deletion of the CDKN2A locus or mutations in the B-RAF and N-RAS genes. Microarray data for eight selected genes were validated with an extended number of cell lines using quantitative real-time polymerase chain reaction. The upregulated genes in cell lines with the deletion besides others included MAGE A2 [fold change 128, 95% confidence interval (CI) 82.8-172.2; t-test P=0.0041, MAGE A6 (fold change 623, 95% CI 473.4-772.1; Mest P=0.001), MAGE A 12 (fold change 90, 95% CI 65.1-115.5; t-test P=0.001) and dopachrome tautomerase (fold change 42, 95% CI 32.5-51.8; t-test P=0.001). Downregulated genes included interleukin 18 (fold change 489, 95% CI 146.4-831.2; t-test P=0.04), ID2 (fold change 3, 95% CI 2.2-4.9; t-test P=0.001), KLF4 (fold change 9, 95% CI 4.3-14.7; P=0.01) and CD24 antigen (fold change 1308, 95% CI 766.0-1850.8; t-test P=0.01). The upregulated genes common to cell lines with homozygous deletion of the CDKN2A gene and mutations in B-RAF and N-RAS gene included those that are involved in RAS/RAF/MEK/ERK pathways. Our results highlight effects of homozygous deletion of the CDKN2A locus on global gene expression
    Type of Publication: Journal article published
    PubMed ID: 16845325
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  • 9
    Keywords: CELLS ; tumor ; TUMOR-CELLS ; BLOOD ; Germany ; DISEASE ; PATIENT ; RESPONSES ; IFN-GAMMA ; DENDRITIC CELLS ; T cells ; T-CELLS ; treatment ; ASSOCIATION ; bone marrow ; BONE-MARROW ; BREAST-CANCER ; STAGE ; MELANOMA ; Jun ; MALIGNANT-MELANOMA ; CANCER PATIENTS ; PERIPHERAL-BLOOD ; HIGH-FREQUENCIES ; BONE ; peripheral blood ; stage III
    Abstract: Using IFN-gamma enzyme-linked immunospot, we investigated reactivity of T cells from bone marrow and peripheral blood to melanoma lysate-pulsed autologous dendritic cells in 40 melanoma patients. Melanoma-reactive T cells were present in the bone marrow of seven patients and in peripheral blood of four patients. In the bone marrow, melanoma-reactive T cells were present in 6 of 21 stage IV patients and in I of 10 stage III patients, whereas none were detected in stage I to II patients (0 of 9). The occurrence of tumor-reactive bone marrow T cells in melanoma patients was associated with advanced disease stage, disease duration and tumor load, and independent of treatment. These findings provide new insights into the generation of T-cell responses in melanoma patients
    Type of Publication: Journal article published
    PubMed ID: 16778169
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  • 10
    Keywords: ONCOLOGY ; CELLS ; USA ; immunology
    Type of Publication: Meeting abstract published
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