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106 Interferon-Producing Killer Dendritic Cells and Natural Killer Cells Response to Interleukin-15 Liver Gene Transfer
Abstracts / Cytokine 39 (2007) 1–49 Interleukin (IL)-22 is a Th17 derived cytokine recently reported to induce in vitro and in vivo an inflammatory-like phenotype bearing analogies with psoriatic skin lesions. In the present study, we assessed the presence of IL-22 and its receptors in skin lesions, skin-derived T cells, and sera from patients with psoriasis. IL-22 mRNA expression was up-regulated in psoriatic skin lesions compared to normal skin, whereas IL-22 mRNA levels in peripheral blood mononuclear cells from psoriatic patients and normal subjects were comparable. Circulating IL-22 levels were significantly higher in psoriatic patients than in normal subjects. T cells infiltrating psoriatic skin produced higher levels of IL-22 than peripheral T cells derived from the same patients. On the other hand, IL-10 was expressed at a similar level in skin biopsies and peripheral blood mononuclear cells of psoriatic patients and normal subjects. Finally, we showed that supernatants of lesional psoriatic skin-infiltrating T cells induced an inflammatory response on normal human epidermal keratinocytes resembling psoriatic lesions. Taken together, the results reported in this study suggest that IL-22 is a T cell-derived cytokine produced in the skin that is potentially involved in initiation and/or maintenance of the pathogenesis of psoriasis.
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taking into account that NK1.1+ cells are absent in IL-15 / mice. An expression cassette encoding human IL-15 (hIL-15) has been transferred by hydrodynamic injection into the liver of mice, resulting in transient expression of the cytokine that peaks in plasma 8 h after injection and is detectable during the first 24–48 h. hIL-15 hydrodynamic gene transfer resulted in an expansion of total NK cells and IKDCs. Adoptively transferred NK cells and IKDCs proliferated in response to hydrodynamic injection of hIL-15, indicating that numeric increases are at least in part the result of proliferation from already differentiated cells. IKDCs were detectable under baseline conditions both in the liver and in the spleen but local numeric expansions were more dramatic in the IL-15 gene-transferred hepatic tissue. The attained expansion of these leukocytes is accompanied by enhanced cytolytic activity against YAC-1 cells and increased surface expression of TRAIL and CD137, but did not augment IFNc production on per cell basis. This first evidence of a functional link between circulating IL-15 and IKDCs opens new possibilities to study the biology and potential applications of this minority cell subset. doi:10.1016/j.cyto.2007.07.111
doi:10.1016/j.cyto.2007.07.109
105 Reversal of Chronic Colitis-Associated Colon Carcinoma Progression by Tumor Necrosis Factor Blockade Naofumi Mukaida, Boryana K. Popivanova, Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan Patients with ulcerative colitis frequently develop colon carcinoma. Repeated dextran sodium sulfate (DSS) ingestion after azoxymethane administration, causes in rodents, severe gastrointestinal mucosal damage and subsequently multiple tumors in colon, recapitulating ulcerative colitis-associated colon carcinogenesis. Tumor necrosis factor (TNF)-alpha was expressed in the lamina propria and submucosa tissues of the colon, with intracolonic infiltration of TNF receptor p55 (TNF-Rp55)-expressing mononuclear cells. Gene ablation of TNF-Rp55 reduced mucosal damage and decreased macrophage and neutrophil infiltration in the early phase, and subsequently attenuated tumor formation with reduction in nuclear beta-catenin accumulation and COX-2 expression by macrophages and neutrophils. Moreover, administration of Etanercept, a specific antagonist of TNF-alpha, even after multiple macroscopic colon tumors develop, remarkably reduced the numbers and size of tumors, together with reduced COX-2 expression, neovascularization, and nuclear beta-catenin accumulation. Thus, TNF-alpha blockade may be effective for treatment as well as prevention of inflammation-associated colorectal carcinogenensis. doi:10.1016/j.cyto.2007.07.110
106 Interferon-Producing Killer Dendritic Cells and Natural Killer Cells Response to Interleukin-15 Liver Gene Transfer Oihana Murillo 1, Ainhoa Arina 1, Juan Dubrot 1, Arantza Azpilikueta 1, Izaskun Gabari 1, Carlos Alfaro 1, Carmen Berasain 1, Sandra HervasStubbs 1, Jose´ L. Perez Gracia 2, Jesu´s Prieto 1,2, Ignacio Melero 1,2, Silvano Ferrini 3, 1 Centro de investigacio´n Me´dica Aplicada (CIMA), Pamplona, Navarra, Spain, 2 Clı´nica Universitaria, Pamplona, Navarra, Spain, 3 Immunological Therapy, Istituto Nazionale per la Ricerca sul Cancro (IST-Genova), Genova, Italy The surface phenotype CD3-NK1.1+DX5+CD11cintB220+GR1- has been recently ascribed to a novel subset of mouse leukocytes termed Interferon-producing Killer Dendritic Cells (IKDCs) that shares functions with NK cells and dendritic cells (DCs). IL-15 is a critical cytokine for differentiation, proliferation and survival of NK cells and conceivably for IKDC,
107 Constitutive Expression of IL-32 Characterizes a Unique Subset of Human Dendritic Cells Receptive to the Venezuelan Equine Encephalitis Virus-Derived Replicon Vector Edward L. Nelson 1,2,3, Kevin P. Nishimoto 2, Stephen Hou 1, Charles A. Dinarello 4, 1 Department of Medicine, Division of Hematology/Oncology, School of Medicine, Irvine, CA, USA, 2 Molecular Biology and Biochemistry, School of Biological Sciences, Irvine, CA, USA, 3 Center for Immunology University of California, Irvine, CA, USA, 4 University of Colorado, Health Science Center, Denver, CO, USA Establishing successful immunotherapeutic strategies utilizing dendritic cells (DC), the most potent-antigen presenting cell, largely depends on understanding the requirements necessary for optimal DC function. We and others have reported that the Venezuelan Equine Encephalitis (VEE) replicon particle (VRP) vector system has conserved tropism for murine, rat, and human DCs. However the DC subset(s) and functional capacities are not fully understood. The VRP vector system has in vitro tropism for a subset of human immature monocyte-derived DCs (M-DCs); therefore, we developed a novel technique to isolate this VRP receptive DC subset for further characterization. An evaluation of VRP receptive and non-receptive M-DC subsets by microarray revealed distinct differences in gene expression profiles with >700 significantly expressed genes (0.001 6 P value, PPDE P 0.98) between cellular subsets. Notably in the receptive DC population, the NK4 transcript was significantly increased and accompanied by protein expression solely in the receptive DC subset. The NK4 gene has recently been identified as encoding a recently described cytokine, interleukin 32. These data provide the initial characterization of a new subset of myeloid DCs targeted by this vector with constitutive IL-32 expression, provides new insights into human DC biology, and opens future studies into the mechanisms employed by this exceptionally potent immunotherapeutic vector system. doi:10.1016/j.cyto.2007.07.112
108 Human Cell-Expressed IL-12 has Enhanced Pro-Inflammatory Activity Rosie Newman, Hui Jiang, Kate Liddell, Linda Crofts, Raina Simpson, Denese Marks, Apollo Cytokine Research Pty Ltd, Sydney, NSW, Australia IL-12 is a pro-inflammatory cytokine produced in response to pathogenic organisms, and a key regulator of innate and adaptive immune response. In particular IL-12 stimulates T-cells and natural killer cells (NK), leading to production of interferon-gamma (IFN-c) and induction of cell mediated immune responses. Human cell-expressed IL-12 (IL-12hcx)
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taking into account that NK1.1+ cells are absent in IL-15 / mice. An expression cassette encoding human IL-15 (hIL-15) has been transferred by hydrodynamic injection into the liver of mice, resulting in transient expression of the cytokine that peaks in plasma 8 h after injection and is detectable during the first 24–48 h. hIL-15 hydrodynamic gene transfer resulted in an expansion of total NK cells and IKDCs. Adoptively transferred NK cells and IKDCs proliferated in response to hydrodynamic injection of hIL-15, indicating that numeric increases are at least in part the result of proliferation from already differentiated cells. IKDCs were detectable under baseline conditions both in the liver and in the spleen but local numeric expansions were more dramatic in the IL-15 gene-transferred hepatic tissue. The attained expansion of these leukocytes is accompanied by enhanced cytolytic activity against YAC-1 cells and increased surface expression of TRAIL and CD137, but did not augment IFNc production on per cell basis. This first evidence of a functional link between circulating IL-15 and IKDCs opens new possibilities to study the biology and potential applications of this minority cell subset. doi:10.1016/j.cyto.2007.07.111
doi:10.1016/j.cyto.2007.07.109
105 Reversal of Chronic Colitis-Associated Colon Carcinoma Progression by Tumor Necrosis Factor Blockade Naofumi Mukaida, Boryana K. Popivanova, Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan Patients with ulcerative colitis frequently develop colon carcinoma. Repeated dextran sodium sulfate (DSS) ingestion after azoxymethane administration, causes in rodents, severe gastrointestinal mucosal damage and subsequently multiple tumors in colon, recapitulating ulcerative colitis-associated colon carcinogenesis. Tumor necrosis factor (TNF)-alpha was expressed in the lamina propria and submucosa tissues of the colon, with intracolonic infiltration of TNF receptor p55 (TNF-Rp55)-expressing mononuclear cells. Gene ablation of TNF-Rp55 reduced mucosal damage and decreased macrophage and neutrophil infiltration in the early phase, and subsequently attenuated tumor formation with reduction in nuclear beta-catenin accumulation and COX-2 expression by macrophages and neutrophils. Moreover, administration of Etanercept, a specific antagonist of TNF-alpha, even after multiple macroscopic colon tumors develop, remarkably reduced the numbers and size of tumors, together with reduced COX-2 expression, neovascularization, and nuclear beta-catenin accumulation. Thus, TNF-alpha blockade may be effective for treatment as well as prevention of inflammation-associated colorectal carcinogenensis. doi:10.1016/j.cyto.2007.07.110
106 Interferon-Producing Killer Dendritic Cells and Natural Killer Cells Response to Interleukin-15 Liver Gene Transfer Oihana Murillo 1, Ainhoa Arina 1, Juan Dubrot 1, Arantza Azpilikueta 1, Izaskun Gabari 1, Carlos Alfaro 1, Carmen Berasain 1, Sandra HervasStubbs 1, Jose´ L. Perez Gracia 2, Jesu´s Prieto 1,2, Ignacio Melero 1,2, Silvano Ferrini 3, 1 Centro de investigacio´n Me´dica Aplicada (CIMA), Pamplona, Navarra, Spain, 2 Clı´nica Universitaria, Pamplona, Navarra, Spain, 3 Immunological Therapy, Istituto Nazionale per la Ricerca sul Cancro (IST-Genova), Genova, Italy The surface phenotype CD3-NK1.1+DX5+CD11cintB220+GR1- has been recently ascribed to a novel subset of mouse leukocytes termed Interferon-producing Killer Dendritic Cells (IKDCs) that shares functions with NK cells and dendritic cells (DCs). IL-15 is a critical cytokine for differentiation, proliferation and survival of NK cells and conceivably for IKDC,
107 Constitutive Expression of IL-32 Characterizes a Unique Subset of Human Dendritic Cells Receptive to the Venezuelan Equine Encephalitis Virus-Derived Replicon Vector Edward L. Nelson 1,2,3, Kevin P. Nishimoto 2, Stephen Hou 1, Charles A. Dinarello 4, 1 Department of Medicine, Division of Hematology/Oncology, School of Medicine, Irvine, CA, USA, 2 Molecular Biology and Biochemistry, School of Biological Sciences, Irvine, CA, USA, 3 Center for Immunology University of California, Irvine, CA, USA, 4 University of Colorado, Health Science Center, Denver, CO, USA Establishing successful immunotherapeutic strategies utilizing dendritic cells (DC), the most potent-antigen presenting cell, largely depends on understanding the requirements necessary for optimal DC function. We and others have reported that the Venezuelan Equine Encephalitis (VEE) replicon particle (VRP) vector system has conserved tropism for murine, rat, and human DCs. However the DC subset(s) and functional capacities are not fully understood. The VRP vector system has in vitro tropism for a subset of human immature monocyte-derived DCs (M-DCs); therefore, we developed a novel technique to isolate this VRP receptive DC subset for further characterization. An evaluation of VRP receptive and non-receptive M-DC subsets by microarray revealed distinct differences in gene expression profiles with >700 significantly expressed genes (0.001 6 P value, PPDE P 0.98) between cellular subsets. Notably in the receptive DC population, the NK4 transcript was significantly increased and accompanied by protein expression solely in the receptive DC subset. The NK4 gene has recently been identified as encoding a recently described cytokine, interleukin 32. These data provide the initial characterization of a new subset of myeloid DCs targeted by this vector with constitutive IL-32 expression, provides new insights into human DC biology, and opens future studies into the mechanisms employed by this exceptionally potent immunotherapeutic vector system. doi:10.1016/j.cyto.2007.07.112
108 Human Cell-Expressed IL-12 has Enhanced Pro-Inflammatory Activity Rosie Newman, Hui Jiang, Kate Liddell, Linda Crofts, Raina Simpson, Denese Marks, Apollo Cytokine Research Pty Ltd, Sydney, NSW, Australia IL-12 is a pro-inflammatory cytokine produced in response to pathogenic organisms, and a key regulator of innate and adaptive immune response. In particular IL-12 stimulates T-cells and natural killer cells (NK), leading to production of interferon-gamma (IFN-c) and induction of cell mediated immune responses. Human cell-expressed IL-12 (IL-12hcx)