The Experts below are selected from a list of 249 Experts worldwide ranked by ideXlab platform

Roswitha Gropp - One of the best experts on this subject based on the ideXlab platform.

  • Design and validation of a disease network of inflammatory processes in the NSG-UC mouse model
    Journal of Translational Medicine, 2017
    Co-Authors: Henrika Jodeleit, Pia Palamides, Matthias Siebeck, Florian Beigel, Thomas Mueller, Eckhard Wolf, Roswitha Gropp
    Abstract:

    Background Ulcerative colitis (UC) is a highly progressive inflammatory disease that requires the interaction of epithelial, immune, endothelial and muscle cells and fibroblasts. Previous studies suggested two inflammatory conditions in UC-patients: ‘acute’ and ‘remodeling’ and that the design of a disease network might improve the understanding of the inflammatory processes. The objective of the study was to design and validate a disease network in the NOD-SCID IL2rγ^null (NSG)-UC mouse model to get a better understanding of the inflammatory processes. Methods Leukocytes were isolated from the spleen of NSG-UC mice and subjected to flow cytometric analysis. RT-PCR and RNAseq analysis were performed from distal parts of the colon. Based on these analyses and the effects of interleukins, chemokines and growth factors described in the literature, a disease network was designed. To validate the disease network the effect of infliximab and Pitrakinra was tested in the NSG-UC model. A clinical- and histological score, frequencies of human leukocytes isolated from spleen and mRNA expression levels from distal parts of the colon were determined. Results Analysis of leukocytes isolated from the spleen of challenged NSG-UC mice corroborated CD64, CD163 and CD1a expressing CD14+ monocytes, CD1a expressing CD11b+ macrophages and HGF, TARC, IFNγ and TGFß1 mRNA as inflammatory markers. The disease network suggested that a proinflammatory condition elicited by IL-17c and lipids and relayed by cytotoxic T-cells, Th17 cells and CD1a expressing macrophages and monocytes. Conversely, the remodeling condition was evoked by IL-34 and TARC and promoted by Th2 cells and M2 monocytes. Mice benefitted from treatment with infliximab as indicated by the histological- and clinical score. As predicted by the disease network infliximab reduced the proinflammatory response by suppressing M1 monocytes and CD1a expressing monocytes and macrophages and decreased levels of IFNγ, TARC and HGF mRNA. As predicted by the disease network inflammation aggravated in the presence of Pitrakinra as indicated by the clinical and histological score, elevated frequencies of CD1a expressing macrophages and TNFα and IFNγ mRNA levels. Conclusions The combination of the disease network and the NSG-UC animal model might be developed into a powerful tool to predict efficacy or in-efficacy and potential mechanistic side effects.

  • Design and validation of a disease network of inflammatory processes in the NSG-UC mouse model
    Journal of Translational Medicine, 2017
    Co-Authors: Henrika Jodeleit, Pia Palamides, Matthias Siebeck, Thomas D Mueller, Florian Beigel, Eckhard Wolf, Roswitha Gropp
    Abstract:

    Ulcerative colitis (UC) is a highly progressive inflammatory disease that requires the interaction of epithelial, immune, endothelial and muscle cells and fibroblasts. Previous studies suggested two inflammatory conditions in UC-patients: ‘acute’ and ‘remodeling’ and that the design of a disease network might improve the understanding of the inflammatory processes. The objective of the study was to design and validate a disease network in the NOD-SCID IL2rγnull (NSG)-UC mouse model to get a better understanding of the inflammatory processes. Leukocytes were isolated from the spleen of NSG-UC mice and subjected to flow cytometric analysis. RT-PCR and RNAseq analysis were performed from distal parts of the colon. Based on these analyses and the effects of interleukins, chemokines and growth factors described in the literature, a disease network was designed. To validate the disease network the effect of infliximab and Pitrakinra was tested in the NSG-UC model. A clinical- and histological score, frequencies of human leukocytes isolated from spleen and mRNA expression levels from distal parts of the colon were determined. Analysis of leukocytes isolated from the spleen of challenged NSG-UC mice corroborated CD64, CD163 and CD1a expressing CD14+ monocytes, CD1a expressing CD11b+ macrophages and HGF, TARC, IFNγ and TGFs1 mRNA as inflammatory markers. The disease network suggested that a proinflammatory condition elicited by IL-17c and lipids and relayed by cytotoxic T-cells, Th17 cells and CD1a expressing macrophages and monocytes. Conversely, the remodeling condition was evoked by IL-34 and TARC and promoted by Th2 cells and M2 monocytes. Mice benefitted from treatment with infliximab as indicated by the histological- and clinical score. As predicted by the disease network infliximab reduced the proinflammatory response by suppressing M1 monocytes and CD1a expressing monocytes and macrophages and decreased levels of IFNγ, TARC and HGF mRNA. As predicted by the disease network inflammation aggravated in the presence of Pitrakinra as indicated by the clinical and histological score, elevated frequencies of CD1a expressing macrophages and TNFα and IFNγ mRNA levels. The combination of the disease network and the NSG-UC animal model might be developed into a powerful tool to predict efficacy or in-efficacy and potential mechanistic side effects.

  • MOESM1 of Design and validation of a disease network of inflammatory processes in the NSG-UC mouse model
    2017
    Co-Authors: Henrika Jodeleit, Pia Palamides, Matthias Siebeck, Florian Beigel, Thomas Mueller, Eckhard Wolf, Roswitha Gropp
    Abstract:

    Additional file 1: Figure S1. Gating strategy for human leukocytes isolated from mouse spleen. Table S1. Cellular markers used to define immune cells. Table S2. Monoclonal antibodies used in labelling of surface markers of leukocytes. Table S3. Data set of variables changed upon challenge with ethanol in the NSG-UC mouse model. Table S4. Data set of variables changed upon challenge with ethanol and treated with infliximab. Table S5. Data set of variables changed upon challenge with ethanol and treated with Pitrakinra

  • A mouse model for ulcerative colitis based on NOD-scid IL2R γnull mice reconstituted with peripheral blood mononuclear cells from affected individuals
    Disease Models & Mechanisms, 2016
    Co-Authors: Pia Palamides, Henrika Jodeleit, Michael Föhlinger, Nadja Herbach, Matthias Siebeck, Thomas D Mueller, Florian Beigel, Eckhard Wolf, Roswitha Gropp
    Abstract:

    Animal models reflective of ulcerative colitis (UC) remain a major challenge and yet are crucial to understand mechanisms underlying the onset of disease and inflammatory characteristics of relapses and remission. Mouse models in which colitis-like symptoms are induced by challenge with toxins such as oxazolone, DSS or TNBS have been instrumental in understanding inflammatory processes of UC, however, they neither reflect the heterogeneous patient population observed in UC nor can they be used when inhibitors require high homology between ligands and receptors. In an attempt to overcome these problems we have developed a mouse model which relies on NOD-SCID IL2rγnull mice reconstituted with peripheral blood mononuclear cells derived from patients suffering from UC. Upon challenge with ethanol mice developed colitis-like symptoms and changes of the colon architecture characterized by influx of inflammatory cells, edema, crypt loss, crypt abscesses and epithelial hyperplasia as previously observed in immune-competent mice. TARC, TGFs1 and HGF expression increased in distal parts of the colon. Analysis of human leucocytes isolated from mouse spleen revealed an increase in frequencies of CD1a+ -, CD64+ -, CD163+ -, and TSLPR+ CD14+ monocytes and antigen-experienced CD44+ CD4+ - and CD8+ T-cells in response to ethanol. Analysis of human leucocytes from colon of challenged mice identified CD14+ monocytes and CD11b+ monocytes as predominant populations. RTPCR analysis from distal parts of the colon indicated that IFNγ might be one cytokine driving inflammation. Treatment with infliximab ameliorated symptoms and pathological manifestations whereas Pitrakinra had no therapeutic benefit. Thus, this model is partially reflective of the human disease and might help to increase translatability between animal- and clinical studies.

  • A mouse model for ulcerative colitis based on NOD-scid IL2R γnull mice reconstituted with peripheral blood mononuclear cells from affected individuals
    Disease models & mechanisms, 2016
    Co-Authors: Pia Palamides, Henrika Jodeleit, Michael Föhlinger, Nadja Herbach, Matthias Siebeck, Thomas D Mueller, Florian Beigel, Eckhard Wolf, Roswitha Gropp
    Abstract:

    Animal models reflective of ulcerative colitis (UC) remain a major challenge, and yet are crucial to understand mechanisms underlying the onset of disease and inflammatory characteristics of relapses and remission. Mouse models in which colitis-like symptoms are induced through challenge with toxins such as oxazolone, dextran sodium sulfate (DSS) or 2,4,6-trinitrobenzenesulfonic acid (TNBS) have been instrumental in understanding the inflammatory processes of UC. However, these neither reflect the heterogeneous symptoms observed in the UC-affected population nor can they be used to test the efficacy of inhibitors developed against human targets where high sequence and structural similarity of the respective ligands is lacking. In an attempt to overcome these problems, we have developed a mouse model that relies on NOD-scid IL2R γ(null) mice reconstituted with peripheral blood mononuclear cells derived from UC-affected individuals. Upon challenge with ethanol, mice developed colitis-like symptoms and changes in the colon architecture, characterized by influx of inflammatory cells, edema, crypt loss, crypt abscesses and epithelial hyperplasia, as previously observed in immune-competent mice. TARC, TGFβ1 and HGF expression increased in distal parts of the colon. Analysis of human leucocytes isolated from mouse spleen revealed an increase in frequencies of CD1a+, CD64+, CD163+ and TSLPR+ CD14+ monocytes, and antigen-experienced CD44+ CD4+ and CD8+ T-cells in response to ethanol. Analysis of human leucocytes from the colon of challenged mice identified CD14+ monocytes and CD11b+ monocytes as the predominant populations. Quantitative real-time PCR (RT-PCR) analysis from distal parts of the colon indicated that IFNγ might be one of the cytokines driving inflammation. Treatment with infliximab ameliorated symptoms and pathological manifestations, whereas Pitrakinra had no therapeutic benefit. Thus, this model is partially reflective of the human disease and might help to increase the translation of animal and clinical studies.

Eckhard Wolf - One of the best experts on this subject based on the ideXlab platform.

  • Design and validation of a disease network of inflammatory processes in the NSG-UC mouse model
    Journal of Translational Medicine, 2017
    Co-Authors: Henrika Jodeleit, Pia Palamides, Matthias Siebeck, Florian Beigel, Thomas Mueller, Eckhard Wolf, Roswitha Gropp
    Abstract:

    Background Ulcerative colitis (UC) is a highly progressive inflammatory disease that requires the interaction of epithelial, immune, endothelial and muscle cells and fibroblasts. Previous studies suggested two inflammatory conditions in UC-patients: ‘acute’ and ‘remodeling’ and that the design of a disease network might improve the understanding of the inflammatory processes. The objective of the study was to design and validate a disease network in the NOD-SCID IL2rγ^null (NSG)-UC mouse model to get a better understanding of the inflammatory processes. Methods Leukocytes were isolated from the spleen of NSG-UC mice and subjected to flow cytometric analysis. RT-PCR and RNAseq analysis were performed from distal parts of the colon. Based on these analyses and the effects of interleukins, chemokines and growth factors described in the literature, a disease network was designed. To validate the disease network the effect of infliximab and Pitrakinra was tested in the NSG-UC model. A clinical- and histological score, frequencies of human leukocytes isolated from spleen and mRNA expression levels from distal parts of the colon were determined. Results Analysis of leukocytes isolated from the spleen of challenged NSG-UC mice corroborated CD64, CD163 and CD1a expressing CD14+ monocytes, CD1a expressing CD11b+ macrophages and HGF, TARC, IFNγ and TGFß1 mRNA as inflammatory markers. The disease network suggested that a proinflammatory condition elicited by IL-17c and lipids and relayed by cytotoxic T-cells, Th17 cells and CD1a expressing macrophages and monocytes. Conversely, the remodeling condition was evoked by IL-34 and TARC and promoted by Th2 cells and M2 monocytes. Mice benefitted from treatment with infliximab as indicated by the histological- and clinical score. As predicted by the disease network infliximab reduced the proinflammatory response by suppressing M1 monocytes and CD1a expressing monocytes and macrophages and decreased levels of IFNγ, TARC and HGF mRNA. As predicted by the disease network inflammation aggravated in the presence of Pitrakinra as indicated by the clinical and histological score, elevated frequencies of CD1a expressing macrophages and TNFα and IFNγ mRNA levels. Conclusions The combination of the disease network and the NSG-UC animal model might be developed into a powerful tool to predict efficacy or in-efficacy and potential mechanistic side effects.

  • Design and validation of a disease network of inflammatory processes in the NSG-UC mouse model
    Journal of Translational Medicine, 2017
    Co-Authors: Henrika Jodeleit, Pia Palamides, Matthias Siebeck, Thomas D Mueller, Florian Beigel, Eckhard Wolf, Roswitha Gropp
    Abstract:

    Ulcerative colitis (UC) is a highly progressive inflammatory disease that requires the interaction of epithelial, immune, endothelial and muscle cells and fibroblasts. Previous studies suggested two inflammatory conditions in UC-patients: ‘acute’ and ‘remodeling’ and that the design of a disease network might improve the understanding of the inflammatory processes. The objective of the study was to design and validate a disease network in the NOD-SCID IL2rγnull (NSG)-UC mouse model to get a better understanding of the inflammatory processes. Leukocytes were isolated from the spleen of NSG-UC mice and subjected to flow cytometric analysis. RT-PCR and RNAseq analysis were performed from distal parts of the colon. Based on these analyses and the effects of interleukins, chemokines and growth factors described in the literature, a disease network was designed. To validate the disease network the effect of infliximab and Pitrakinra was tested in the NSG-UC model. A clinical- and histological score, frequencies of human leukocytes isolated from spleen and mRNA expression levels from distal parts of the colon were determined. Analysis of leukocytes isolated from the spleen of challenged NSG-UC mice corroborated CD64, CD163 and CD1a expressing CD14+ monocytes, CD1a expressing CD11b+ macrophages and HGF, TARC, IFNγ and TGFs1 mRNA as inflammatory markers. The disease network suggested that a proinflammatory condition elicited by IL-17c and lipids and relayed by cytotoxic T-cells, Th17 cells and CD1a expressing macrophages and monocytes. Conversely, the remodeling condition was evoked by IL-34 and TARC and promoted by Th2 cells and M2 monocytes. Mice benefitted from treatment with infliximab as indicated by the histological- and clinical score. As predicted by the disease network infliximab reduced the proinflammatory response by suppressing M1 monocytes and CD1a expressing monocytes and macrophages and decreased levels of IFNγ, TARC and HGF mRNA. As predicted by the disease network inflammation aggravated in the presence of Pitrakinra as indicated by the clinical and histological score, elevated frequencies of CD1a expressing macrophages and TNFα and IFNγ mRNA levels. The combination of the disease network and the NSG-UC animal model might be developed into a powerful tool to predict efficacy or in-efficacy and potential mechanistic side effects.

  • MOESM1 of Design and validation of a disease network of inflammatory processes in the NSG-UC mouse model
    2017
    Co-Authors: Henrika Jodeleit, Pia Palamides, Matthias Siebeck, Florian Beigel, Thomas Mueller, Eckhard Wolf, Roswitha Gropp
    Abstract:

    Additional file 1: Figure S1. Gating strategy for human leukocytes isolated from mouse spleen. Table S1. Cellular markers used to define immune cells. Table S2. Monoclonal antibodies used in labelling of surface markers of leukocytes. Table S3. Data set of variables changed upon challenge with ethanol in the NSG-UC mouse model. Table S4. Data set of variables changed upon challenge with ethanol and treated with infliximab. Table S5. Data set of variables changed upon challenge with ethanol and treated with Pitrakinra

  • A mouse model for ulcerative colitis based on NOD-scid IL2R γnull mice reconstituted with peripheral blood mononuclear cells from affected individuals
    Disease Models & Mechanisms, 2016
    Co-Authors: Pia Palamides, Henrika Jodeleit, Michael Föhlinger, Nadja Herbach, Matthias Siebeck, Thomas D Mueller, Florian Beigel, Eckhard Wolf, Roswitha Gropp
    Abstract:

    Animal models reflective of ulcerative colitis (UC) remain a major challenge and yet are crucial to understand mechanisms underlying the onset of disease and inflammatory characteristics of relapses and remission. Mouse models in which colitis-like symptoms are induced by challenge with toxins such as oxazolone, DSS or TNBS have been instrumental in understanding inflammatory processes of UC, however, they neither reflect the heterogeneous patient population observed in UC nor can they be used when inhibitors require high homology between ligands and receptors. In an attempt to overcome these problems we have developed a mouse model which relies on NOD-SCID IL2rγnull mice reconstituted with peripheral blood mononuclear cells derived from patients suffering from UC. Upon challenge with ethanol mice developed colitis-like symptoms and changes of the colon architecture characterized by influx of inflammatory cells, edema, crypt loss, crypt abscesses and epithelial hyperplasia as previously observed in immune-competent mice. TARC, TGFs1 and HGF expression increased in distal parts of the colon. Analysis of human leucocytes isolated from mouse spleen revealed an increase in frequencies of CD1a+ -, CD64+ -, CD163+ -, and TSLPR+ CD14+ monocytes and antigen-experienced CD44+ CD4+ - and CD8+ T-cells in response to ethanol. Analysis of human leucocytes from colon of challenged mice identified CD14+ monocytes and CD11b+ monocytes as predominant populations. RTPCR analysis from distal parts of the colon indicated that IFNγ might be one cytokine driving inflammation. Treatment with infliximab ameliorated symptoms and pathological manifestations whereas Pitrakinra had no therapeutic benefit. Thus, this model is partially reflective of the human disease and might help to increase translatability between animal- and clinical studies.

  • A mouse model for ulcerative colitis based on NOD-scid IL2R γnull mice reconstituted with peripheral blood mononuclear cells from affected individuals
    Disease models & mechanisms, 2016
    Co-Authors: Pia Palamides, Henrika Jodeleit, Michael Föhlinger, Nadja Herbach, Matthias Siebeck, Thomas D Mueller, Florian Beigel, Eckhard Wolf, Roswitha Gropp
    Abstract:

    Animal models reflective of ulcerative colitis (UC) remain a major challenge, and yet are crucial to understand mechanisms underlying the onset of disease and inflammatory characteristics of relapses and remission. Mouse models in which colitis-like symptoms are induced through challenge with toxins such as oxazolone, dextran sodium sulfate (DSS) or 2,4,6-trinitrobenzenesulfonic acid (TNBS) have been instrumental in understanding the inflammatory processes of UC. However, these neither reflect the heterogeneous symptoms observed in the UC-affected population nor can they be used to test the efficacy of inhibitors developed against human targets where high sequence and structural similarity of the respective ligands is lacking. In an attempt to overcome these problems, we have developed a mouse model that relies on NOD-scid IL2R γ(null) mice reconstituted with peripheral blood mononuclear cells derived from UC-affected individuals. Upon challenge with ethanol, mice developed colitis-like symptoms and changes in the colon architecture, characterized by influx of inflammatory cells, edema, crypt loss, crypt abscesses and epithelial hyperplasia, as previously observed in immune-competent mice. TARC, TGFβ1 and HGF expression increased in distal parts of the colon. Analysis of human leucocytes isolated from mouse spleen revealed an increase in frequencies of CD1a+, CD64+, CD163+ and TSLPR+ CD14+ monocytes, and antigen-experienced CD44+ CD4+ and CD8+ T-cells in response to ethanol. Analysis of human leucocytes from the colon of challenged mice identified CD14+ monocytes and CD11b+ monocytes as the predominant populations. Quantitative real-time PCR (RT-PCR) analysis from distal parts of the colon indicated that IFNγ might be one of the cytokines driving inflammation. Treatment with infliximab ameliorated symptoms and pathological manifestations, whereas Pitrakinra had no therapeutic benefit. Thus, this model is partially reflective of the human disease and might help to increase the translation of animal and clinical studies.

Matthias Siebeck - One of the best experts on this subject based on the ideXlab platform.

  • Design and validation of a disease network of inflammatory processes in the NSG-UC mouse model
    Journal of Translational Medicine, 2017
    Co-Authors: Henrika Jodeleit, Pia Palamides, Matthias Siebeck, Florian Beigel, Thomas Mueller, Eckhard Wolf, Roswitha Gropp
    Abstract:

    Background Ulcerative colitis (UC) is a highly progressive inflammatory disease that requires the interaction of epithelial, immune, endothelial and muscle cells and fibroblasts. Previous studies suggested two inflammatory conditions in UC-patients: ‘acute’ and ‘remodeling’ and that the design of a disease network might improve the understanding of the inflammatory processes. The objective of the study was to design and validate a disease network in the NOD-SCID IL2rγ^null (NSG)-UC mouse model to get a better understanding of the inflammatory processes. Methods Leukocytes were isolated from the spleen of NSG-UC mice and subjected to flow cytometric analysis. RT-PCR and RNAseq analysis were performed from distal parts of the colon. Based on these analyses and the effects of interleukins, chemokines and growth factors described in the literature, a disease network was designed. To validate the disease network the effect of infliximab and Pitrakinra was tested in the NSG-UC model. A clinical- and histological score, frequencies of human leukocytes isolated from spleen and mRNA expression levels from distal parts of the colon were determined. Results Analysis of leukocytes isolated from the spleen of challenged NSG-UC mice corroborated CD64, CD163 and CD1a expressing CD14+ monocytes, CD1a expressing CD11b+ macrophages and HGF, TARC, IFNγ and TGFß1 mRNA as inflammatory markers. The disease network suggested that a proinflammatory condition elicited by IL-17c and lipids and relayed by cytotoxic T-cells, Th17 cells and CD1a expressing macrophages and monocytes. Conversely, the remodeling condition was evoked by IL-34 and TARC and promoted by Th2 cells and M2 monocytes. Mice benefitted from treatment with infliximab as indicated by the histological- and clinical score. As predicted by the disease network infliximab reduced the proinflammatory response by suppressing M1 monocytes and CD1a expressing monocytes and macrophages and decreased levels of IFNγ, TARC and HGF mRNA. As predicted by the disease network inflammation aggravated in the presence of Pitrakinra as indicated by the clinical and histological score, elevated frequencies of CD1a expressing macrophages and TNFα and IFNγ mRNA levels. Conclusions The combination of the disease network and the NSG-UC animal model might be developed into a powerful tool to predict efficacy or in-efficacy and potential mechanistic side effects.

  • Design and validation of a disease network of inflammatory processes in the NSG-UC mouse model
    Journal of Translational Medicine, 2017
    Co-Authors: Henrika Jodeleit, Pia Palamides, Matthias Siebeck, Thomas D Mueller, Florian Beigel, Eckhard Wolf, Roswitha Gropp
    Abstract:

    Ulcerative colitis (UC) is a highly progressive inflammatory disease that requires the interaction of epithelial, immune, endothelial and muscle cells and fibroblasts. Previous studies suggested two inflammatory conditions in UC-patients: ‘acute’ and ‘remodeling’ and that the design of a disease network might improve the understanding of the inflammatory processes. The objective of the study was to design and validate a disease network in the NOD-SCID IL2rγnull (NSG)-UC mouse model to get a better understanding of the inflammatory processes. Leukocytes were isolated from the spleen of NSG-UC mice and subjected to flow cytometric analysis. RT-PCR and RNAseq analysis were performed from distal parts of the colon. Based on these analyses and the effects of interleukins, chemokines and growth factors described in the literature, a disease network was designed. To validate the disease network the effect of infliximab and Pitrakinra was tested in the NSG-UC model. A clinical- and histological score, frequencies of human leukocytes isolated from spleen and mRNA expression levels from distal parts of the colon were determined. Analysis of leukocytes isolated from the spleen of challenged NSG-UC mice corroborated CD64, CD163 and CD1a expressing CD14+ monocytes, CD1a expressing CD11b+ macrophages and HGF, TARC, IFNγ and TGFs1 mRNA as inflammatory markers. The disease network suggested that a proinflammatory condition elicited by IL-17c and lipids and relayed by cytotoxic T-cells, Th17 cells and CD1a expressing macrophages and monocytes. Conversely, the remodeling condition was evoked by IL-34 and TARC and promoted by Th2 cells and M2 monocytes. Mice benefitted from treatment with infliximab as indicated by the histological- and clinical score. As predicted by the disease network infliximab reduced the proinflammatory response by suppressing M1 monocytes and CD1a expressing monocytes and macrophages and decreased levels of IFNγ, TARC and HGF mRNA. As predicted by the disease network inflammation aggravated in the presence of Pitrakinra as indicated by the clinical and histological score, elevated frequencies of CD1a expressing macrophages and TNFα and IFNγ mRNA levels. The combination of the disease network and the NSG-UC animal model might be developed into a powerful tool to predict efficacy or in-efficacy and potential mechanistic side effects.

  • MOESM1 of Design and validation of a disease network of inflammatory processes in the NSG-UC mouse model
    2017
    Co-Authors: Henrika Jodeleit, Pia Palamides, Matthias Siebeck, Florian Beigel, Thomas Mueller, Eckhard Wolf, Roswitha Gropp
    Abstract:

    Additional file 1: Figure S1. Gating strategy for human leukocytes isolated from mouse spleen. Table S1. Cellular markers used to define immune cells. Table S2. Monoclonal antibodies used in labelling of surface markers of leukocytes. Table S3. Data set of variables changed upon challenge with ethanol in the NSG-UC mouse model. Table S4. Data set of variables changed upon challenge with ethanol and treated with infliximab. Table S5. Data set of variables changed upon challenge with ethanol and treated with Pitrakinra

  • A mouse model for ulcerative colitis based on NOD-scid IL2R γnull mice reconstituted with peripheral blood mononuclear cells from affected individuals
    Disease Models & Mechanisms, 2016
    Co-Authors: Pia Palamides, Henrika Jodeleit, Michael Föhlinger, Nadja Herbach, Matthias Siebeck, Thomas D Mueller, Florian Beigel, Eckhard Wolf, Roswitha Gropp
    Abstract:

    Animal models reflective of ulcerative colitis (UC) remain a major challenge and yet are crucial to understand mechanisms underlying the onset of disease and inflammatory characteristics of relapses and remission. Mouse models in which colitis-like symptoms are induced by challenge with toxins such as oxazolone, DSS or TNBS have been instrumental in understanding inflammatory processes of UC, however, they neither reflect the heterogeneous patient population observed in UC nor can they be used when inhibitors require high homology between ligands and receptors. In an attempt to overcome these problems we have developed a mouse model which relies on NOD-SCID IL2rγnull mice reconstituted with peripheral blood mononuclear cells derived from patients suffering from UC. Upon challenge with ethanol mice developed colitis-like symptoms and changes of the colon architecture characterized by influx of inflammatory cells, edema, crypt loss, crypt abscesses and epithelial hyperplasia as previously observed in immune-competent mice. TARC, TGFs1 and HGF expression increased in distal parts of the colon. Analysis of human leucocytes isolated from mouse spleen revealed an increase in frequencies of CD1a+ -, CD64+ -, CD163+ -, and TSLPR+ CD14+ monocytes and antigen-experienced CD44+ CD4+ - and CD8+ T-cells in response to ethanol. Analysis of human leucocytes from colon of challenged mice identified CD14+ monocytes and CD11b+ monocytes as predominant populations. RTPCR analysis from distal parts of the colon indicated that IFNγ might be one cytokine driving inflammation. Treatment with infliximab ameliorated symptoms and pathological manifestations whereas Pitrakinra had no therapeutic benefit. Thus, this model is partially reflective of the human disease and might help to increase translatability between animal- and clinical studies.

  • A mouse model for ulcerative colitis based on NOD-scid IL2R γnull mice reconstituted with peripheral blood mononuclear cells from affected individuals
    Disease models & mechanisms, 2016
    Co-Authors: Pia Palamides, Henrika Jodeleit, Michael Föhlinger, Nadja Herbach, Matthias Siebeck, Thomas D Mueller, Florian Beigel, Eckhard Wolf, Roswitha Gropp
    Abstract:

    Animal models reflective of ulcerative colitis (UC) remain a major challenge, and yet are crucial to understand mechanisms underlying the onset of disease and inflammatory characteristics of relapses and remission. Mouse models in which colitis-like symptoms are induced through challenge with toxins such as oxazolone, dextran sodium sulfate (DSS) or 2,4,6-trinitrobenzenesulfonic acid (TNBS) have been instrumental in understanding the inflammatory processes of UC. However, these neither reflect the heterogeneous symptoms observed in the UC-affected population nor can they be used to test the efficacy of inhibitors developed against human targets where high sequence and structural similarity of the respective ligands is lacking. In an attempt to overcome these problems, we have developed a mouse model that relies on NOD-scid IL2R γ(null) mice reconstituted with peripheral blood mononuclear cells derived from UC-affected individuals. Upon challenge with ethanol, mice developed colitis-like symptoms and changes in the colon architecture, characterized by influx of inflammatory cells, edema, crypt loss, crypt abscesses and epithelial hyperplasia, as previously observed in immune-competent mice. TARC, TGFβ1 and HGF expression increased in distal parts of the colon. Analysis of human leucocytes isolated from mouse spleen revealed an increase in frequencies of CD1a+, CD64+, CD163+ and TSLPR+ CD14+ monocytes, and antigen-experienced CD44+ CD4+ and CD8+ T-cells in response to ethanol. Analysis of human leucocytes from the colon of challenged mice identified CD14+ monocytes and CD11b+ monocytes as the predominant populations. Quantitative real-time PCR (RT-PCR) analysis from distal parts of the colon indicated that IFNγ might be one of the cytokines driving inflammation. Treatment with infliximab ameliorated symptoms and pathological manifestations, whereas Pitrakinra had no therapeutic benefit. Thus, this model is partially reflective of the human disease and might help to increase the translation of animal and clinical studies.

Thomas D Mueller - One of the best experts on this subject based on the ideXlab platform.

  • Design and validation of a disease network of inflammatory processes in the NSG-UC mouse model
    Journal of Translational Medicine, 2017
    Co-Authors: Henrika Jodeleit, Pia Palamides, Matthias Siebeck, Thomas D Mueller, Florian Beigel, Eckhard Wolf, Roswitha Gropp
    Abstract:

    Ulcerative colitis (UC) is a highly progressive inflammatory disease that requires the interaction of epithelial, immune, endothelial and muscle cells and fibroblasts. Previous studies suggested two inflammatory conditions in UC-patients: ‘acute’ and ‘remodeling’ and that the design of a disease network might improve the understanding of the inflammatory processes. The objective of the study was to design and validate a disease network in the NOD-SCID IL2rγnull (NSG)-UC mouse model to get a better understanding of the inflammatory processes. Leukocytes were isolated from the spleen of NSG-UC mice and subjected to flow cytometric analysis. RT-PCR and RNAseq analysis were performed from distal parts of the colon. Based on these analyses and the effects of interleukins, chemokines and growth factors described in the literature, a disease network was designed. To validate the disease network the effect of infliximab and Pitrakinra was tested in the NSG-UC model. A clinical- and histological score, frequencies of human leukocytes isolated from spleen and mRNA expression levels from distal parts of the colon were determined. Analysis of leukocytes isolated from the spleen of challenged NSG-UC mice corroborated CD64, CD163 and CD1a expressing CD14+ monocytes, CD1a expressing CD11b+ macrophages and HGF, TARC, IFNγ and TGFs1 mRNA as inflammatory markers. The disease network suggested that a proinflammatory condition elicited by IL-17c and lipids and relayed by cytotoxic T-cells, Th17 cells and CD1a expressing macrophages and monocytes. Conversely, the remodeling condition was evoked by IL-34 and TARC and promoted by Th2 cells and M2 monocytes. Mice benefitted from treatment with infliximab as indicated by the histological- and clinical score. As predicted by the disease network infliximab reduced the proinflammatory response by suppressing M1 monocytes and CD1a expressing monocytes and macrophages and decreased levels of IFNγ, TARC and HGF mRNA. As predicted by the disease network inflammation aggravated in the presence of Pitrakinra as indicated by the clinical and histological score, elevated frequencies of CD1a expressing macrophages and TNFα and IFNγ mRNA levels. The combination of the disease network and the NSG-UC animal model might be developed into a powerful tool to predict efficacy or in-efficacy and potential mechanistic side effects.

  • A mouse model for ulcerative colitis based on NOD-scid IL2R γnull mice reconstituted with peripheral blood mononuclear cells from affected individuals
    Disease Models & Mechanisms, 2016
    Co-Authors: Pia Palamides, Henrika Jodeleit, Michael Föhlinger, Nadja Herbach, Matthias Siebeck, Thomas D Mueller, Florian Beigel, Eckhard Wolf, Roswitha Gropp
    Abstract:

    Animal models reflective of ulcerative colitis (UC) remain a major challenge and yet are crucial to understand mechanisms underlying the onset of disease and inflammatory characteristics of relapses and remission. Mouse models in which colitis-like symptoms are induced by challenge with toxins such as oxazolone, DSS or TNBS have been instrumental in understanding inflammatory processes of UC, however, they neither reflect the heterogeneous patient population observed in UC nor can they be used when inhibitors require high homology between ligands and receptors. In an attempt to overcome these problems we have developed a mouse model which relies on NOD-SCID IL2rγnull mice reconstituted with peripheral blood mononuclear cells derived from patients suffering from UC. Upon challenge with ethanol mice developed colitis-like symptoms and changes of the colon architecture characterized by influx of inflammatory cells, edema, crypt loss, crypt abscesses and epithelial hyperplasia as previously observed in immune-competent mice. TARC, TGFs1 and HGF expression increased in distal parts of the colon. Analysis of human leucocytes isolated from mouse spleen revealed an increase in frequencies of CD1a+ -, CD64+ -, CD163+ -, and TSLPR+ CD14+ monocytes and antigen-experienced CD44+ CD4+ - and CD8+ T-cells in response to ethanol. Analysis of human leucocytes from colon of challenged mice identified CD14+ monocytes and CD11b+ monocytes as predominant populations. RTPCR analysis from distal parts of the colon indicated that IFNγ might be one cytokine driving inflammation. Treatment with infliximab ameliorated symptoms and pathological manifestations whereas Pitrakinra had no therapeutic benefit. Thus, this model is partially reflective of the human disease and might help to increase translatability between animal- and clinical studies.

  • A mouse model for ulcerative colitis based on NOD-scid IL2R γnull mice reconstituted with peripheral blood mononuclear cells from affected individuals
    Disease models & mechanisms, 2016
    Co-Authors: Pia Palamides, Henrika Jodeleit, Michael Föhlinger, Nadja Herbach, Matthias Siebeck, Thomas D Mueller, Florian Beigel, Eckhard Wolf, Roswitha Gropp
    Abstract:

    Animal models reflective of ulcerative colitis (UC) remain a major challenge, and yet are crucial to understand mechanisms underlying the onset of disease and inflammatory characteristics of relapses and remission. Mouse models in which colitis-like symptoms are induced through challenge with toxins such as oxazolone, dextran sodium sulfate (DSS) or 2,4,6-trinitrobenzenesulfonic acid (TNBS) have been instrumental in understanding the inflammatory processes of UC. However, these neither reflect the heterogeneous symptoms observed in the UC-affected population nor can they be used to test the efficacy of inhibitors developed against human targets where high sequence and structural similarity of the respective ligands is lacking. In an attempt to overcome these problems, we have developed a mouse model that relies on NOD-scid IL2R γ(null) mice reconstituted with peripheral blood mononuclear cells derived from UC-affected individuals. Upon challenge with ethanol, mice developed colitis-like symptoms and changes in the colon architecture, characterized by influx of inflammatory cells, edema, crypt loss, crypt abscesses and epithelial hyperplasia, as previously observed in immune-competent mice. TARC, TGFβ1 and HGF expression increased in distal parts of the colon. Analysis of human leucocytes isolated from mouse spleen revealed an increase in frequencies of CD1a+, CD64+, CD163+ and TSLPR+ CD14+ monocytes, and antigen-experienced CD44+ CD4+ and CD8+ T-cells in response to ethanol. Analysis of human leucocytes from the colon of challenged mice identified CD14+ monocytes and CD11b+ monocytes as the predominant populations. Quantitative real-time PCR (RT-PCR) analysis from distal parts of the colon indicated that IFNγ might be one of the cytokines driving inflammation. Treatment with infliximab ameliorated symptoms and pathological manifestations, whereas Pitrakinra had no therapeutic benefit. Thus, this model is partially reflective of the human disease and might help to increase the translation of animal and clinical studies.

  • NOD-scid IL2R γ^null mice engrafted with human peripheral blood mononuclear cells as a model to test therapeutics targeting human signaling pathways
    Journal of Translational Medicine, 2013
    Co-Authors: Maryam Zadeh-khorasani, Markos Pechlivanis, Matthias Siebeck, Thomas D Mueller, Andreas Wollenberg, Franziska Rueff, Eckhard Wolf, Thomas Nolte, Gert Fricker, Roswitha Gropp
    Abstract:

    Background Animal models of human inflammatory diseases have limited predictive quality for human clinical trials for various reasons including species specific activation mechanisms and the immunological background of the animals which markedly differs from the genetically heterogeneous and often aged patient population. Objective Development of an animal model allowing for testing therapeutics targeting pathways involved in the development of Atopic Dermatitis (AD) with better translatability to the patient. Methods NOD-scid IL2R γ^null mice engrafted with human peripheral blood mononuclear cells (hPBMC) derived from patients suffering from AD and healthy volunteers were treated with IL-4 and the antagonistic IL-4 variant R121/Y124D (Pitrakinra). Levels of human (h)IgE, amount of B-, T- and plasma- cells and ratio of CD4 : CD8 positive cells served as read out for induction and inhibition of cell proliferation and hIgE secretion. Results were compared to in vitro analysis. Results hIgE secretion was induced by IL-4 and inhibited by the IL-4 antagonist Pitrakinra in vivo when formulated with methylcellulose. B-cells proliferated in response to IL-4 in vivo ; the effect was abrogated by Pitrakinra. IL-4 shifted CD4 : CD8 ratios in vitro and in vivo when hPBMC derived from healthy volunteers were used. Pitrakinra reversed the effect. Human PBMC derived from patients with AD remained inert and engrafted mice reflected the individual responses observed in vitro . Conclusion NOD-scid IL2R γ^null mice engrafted with human PBMC reflect the immunological history of the donors and provide a complementary tool to in vitro studies. Thus, studies in this model might provide data with better translatability from bench to bedside.

Pia Palamides - One of the best experts on this subject based on the ideXlab platform.

  • Design and validation of a disease network of inflammatory processes in the NSG-UC mouse model
    Journal of Translational Medicine, 2017
    Co-Authors: Henrika Jodeleit, Pia Palamides, Matthias Siebeck, Florian Beigel, Thomas Mueller, Eckhard Wolf, Roswitha Gropp
    Abstract:

    Background Ulcerative colitis (UC) is a highly progressive inflammatory disease that requires the interaction of epithelial, immune, endothelial and muscle cells and fibroblasts. Previous studies suggested two inflammatory conditions in UC-patients: ‘acute’ and ‘remodeling’ and that the design of a disease network might improve the understanding of the inflammatory processes. The objective of the study was to design and validate a disease network in the NOD-SCID IL2rγ^null (NSG)-UC mouse model to get a better understanding of the inflammatory processes. Methods Leukocytes were isolated from the spleen of NSG-UC mice and subjected to flow cytometric analysis. RT-PCR and RNAseq analysis were performed from distal parts of the colon. Based on these analyses and the effects of interleukins, chemokines and growth factors described in the literature, a disease network was designed. To validate the disease network the effect of infliximab and Pitrakinra was tested in the NSG-UC model. A clinical- and histological score, frequencies of human leukocytes isolated from spleen and mRNA expression levels from distal parts of the colon were determined. Results Analysis of leukocytes isolated from the spleen of challenged NSG-UC mice corroborated CD64, CD163 and CD1a expressing CD14+ monocytes, CD1a expressing CD11b+ macrophages and HGF, TARC, IFNγ and TGFß1 mRNA as inflammatory markers. The disease network suggested that a proinflammatory condition elicited by IL-17c and lipids and relayed by cytotoxic T-cells, Th17 cells and CD1a expressing macrophages and monocytes. Conversely, the remodeling condition was evoked by IL-34 and TARC and promoted by Th2 cells and M2 monocytes. Mice benefitted from treatment with infliximab as indicated by the histological- and clinical score. As predicted by the disease network infliximab reduced the proinflammatory response by suppressing M1 monocytes and CD1a expressing monocytes and macrophages and decreased levels of IFNγ, TARC and HGF mRNA. As predicted by the disease network inflammation aggravated in the presence of Pitrakinra as indicated by the clinical and histological score, elevated frequencies of CD1a expressing macrophages and TNFα and IFNγ mRNA levels. Conclusions The combination of the disease network and the NSG-UC animal model might be developed into a powerful tool to predict efficacy or in-efficacy and potential mechanistic side effects.

  • Design and validation of a disease network of inflammatory processes in the NSG-UC mouse model
    Journal of Translational Medicine, 2017
    Co-Authors: Henrika Jodeleit, Pia Palamides, Matthias Siebeck, Thomas D Mueller, Florian Beigel, Eckhard Wolf, Roswitha Gropp
    Abstract:

    Ulcerative colitis (UC) is a highly progressive inflammatory disease that requires the interaction of epithelial, immune, endothelial and muscle cells and fibroblasts. Previous studies suggested two inflammatory conditions in UC-patients: ‘acute’ and ‘remodeling’ and that the design of a disease network might improve the understanding of the inflammatory processes. The objective of the study was to design and validate a disease network in the NOD-SCID IL2rγnull (NSG)-UC mouse model to get a better understanding of the inflammatory processes. Leukocytes were isolated from the spleen of NSG-UC mice and subjected to flow cytometric analysis. RT-PCR and RNAseq analysis were performed from distal parts of the colon. Based on these analyses and the effects of interleukins, chemokines and growth factors described in the literature, a disease network was designed. To validate the disease network the effect of infliximab and Pitrakinra was tested in the NSG-UC model. A clinical- and histological score, frequencies of human leukocytes isolated from spleen and mRNA expression levels from distal parts of the colon were determined. Analysis of leukocytes isolated from the spleen of challenged NSG-UC mice corroborated CD64, CD163 and CD1a expressing CD14+ monocytes, CD1a expressing CD11b+ macrophages and HGF, TARC, IFNγ and TGFs1 mRNA as inflammatory markers. The disease network suggested that a proinflammatory condition elicited by IL-17c and lipids and relayed by cytotoxic T-cells, Th17 cells and CD1a expressing macrophages and monocytes. Conversely, the remodeling condition was evoked by IL-34 and TARC and promoted by Th2 cells and M2 monocytes. Mice benefitted from treatment with infliximab as indicated by the histological- and clinical score. As predicted by the disease network infliximab reduced the proinflammatory response by suppressing M1 monocytes and CD1a expressing monocytes and macrophages and decreased levels of IFNγ, TARC and HGF mRNA. As predicted by the disease network inflammation aggravated in the presence of Pitrakinra as indicated by the clinical and histological score, elevated frequencies of CD1a expressing macrophages and TNFα and IFNγ mRNA levels. The combination of the disease network and the NSG-UC animal model might be developed into a powerful tool to predict efficacy or in-efficacy and potential mechanistic side effects.

  • MOESM1 of Design and validation of a disease network of inflammatory processes in the NSG-UC mouse model
    2017
    Co-Authors: Henrika Jodeleit, Pia Palamides, Matthias Siebeck, Florian Beigel, Thomas Mueller, Eckhard Wolf, Roswitha Gropp
    Abstract:

    Additional file 1: Figure S1. Gating strategy for human leukocytes isolated from mouse spleen. Table S1. Cellular markers used to define immune cells. Table S2. Monoclonal antibodies used in labelling of surface markers of leukocytes. Table S3. Data set of variables changed upon challenge with ethanol in the NSG-UC mouse model. Table S4. Data set of variables changed upon challenge with ethanol and treated with infliximab. Table S5. Data set of variables changed upon challenge with ethanol and treated with Pitrakinra

  • A mouse model for ulcerative colitis based on NOD-scid IL2R γnull mice reconstituted with peripheral blood mononuclear cells from affected individuals
    Disease Models & Mechanisms, 2016
    Co-Authors: Pia Palamides, Henrika Jodeleit, Michael Föhlinger, Nadja Herbach, Matthias Siebeck, Thomas D Mueller, Florian Beigel, Eckhard Wolf, Roswitha Gropp
    Abstract:

    Animal models reflective of ulcerative colitis (UC) remain a major challenge and yet are crucial to understand mechanisms underlying the onset of disease and inflammatory characteristics of relapses and remission. Mouse models in which colitis-like symptoms are induced by challenge with toxins such as oxazolone, DSS or TNBS have been instrumental in understanding inflammatory processes of UC, however, they neither reflect the heterogeneous patient population observed in UC nor can they be used when inhibitors require high homology between ligands and receptors. In an attempt to overcome these problems we have developed a mouse model which relies on NOD-SCID IL2rγnull mice reconstituted with peripheral blood mononuclear cells derived from patients suffering from UC. Upon challenge with ethanol mice developed colitis-like symptoms and changes of the colon architecture characterized by influx of inflammatory cells, edema, crypt loss, crypt abscesses and epithelial hyperplasia as previously observed in immune-competent mice. TARC, TGFs1 and HGF expression increased in distal parts of the colon. Analysis of human leucocytes isolated from mouse spleen revealed an increase in frequencies of CD1a+ -, CD64+ -, CD163+ -, and TSLPR+ CD14+ monocytes and antigen-experienced CD44+ CD4+ - and CD8+ T-cells in response to ethanol. Analysis of human leucocytes from colon of challenged mice identified CD14+ monocytes and CD11b+ monocytes as predominant populations. RTPCR analysis from distal parts of the colon indicated that IFNγ might be one cytokine driving inflammation. Treatment with infliximab ameliorated symptoms and pathological manifestations whereas Pitrakinra had no therapeutic benefit. Thus, this model is partially reflective of the human disease and might help to increase translatability between animal- and clinical studies.

  • A mouse model for ulcerative colitis based on NOD-scid IL2R γnull mice reconstituted with peripheral blood mononuclear cells from affected individuals
    Disease models & mechanisms, 2016
    Co-Authors: Pia Palamides, Henrika Jodeleit, Michael Föhlinger, Nadja Herbach, Matthias Siebeck, Thomas D Mueller, Florian Beigel, Eckhard Wolf, Roswitha Gropp
    Abstract:

    Animal models reflective of ulcerative colitis (UC) remain a major challenge, and yet are crucial to understand mechanisms underlying the onset of disease and inflammatory characteristics of relapses and remission. Mouse models in which colitis-like symptoms are induced through challenge with toxins such as oxazolone, dextran sodium sulfate (DSS) or 2,4,6-trinitrobenzenesulfonic acid (TNBS) have been instrumental in understanding the inflammatory processes of UC. However, these neither reflect the heterogeneous symptoms observed in the UC-affected population nor can they be used to test the efficacy of inhibitors developed against human targets where high sequence and structural similarity of the respective ligands is lacking. In an attempt to overcome these problems, we have developed a mouse model that relies on NOD-scid IL2R γ(null) mice reconstituted with peripheral blood mononuclear cells derived from UC-affected individuals. Upon challenge with ethanol, mice developed colitis-like symptoms and changes in the colon architecture, characterized by influx of inflammatory cells, edema, crypt loss, crypt abscesses and epithelial hyperplasia, as previously observed in immune-competent mice. TARC, TGFβ1 and HGF expression increased in distal parts of the colon. Analysis of human leucocytes isolated from mouse spleen revealed an increase in frequencies of CD1a+, CD64+, CD163+ and TSLPR+ CD14+ monocytes, and antigen-experienced CD44+ CD4+ and CD8+ T-cells in response to ethanol. Analysis of human leucocytes from the colon of challenged mice identified CD14+ monocytes and CD11b+ monocytes as the predominant populations. Quantitative real-time PCR (RT-PCR) analysis from distal parts of the colon indicated that IFNγ might be one of the cytokines driving inflammation. Treatment with infliximab ameliorated symptoms and pathological manifestations, whereas Pitrakinra had no therapeutic benefit. Thus, this model is partially reflective of the human disease and might help to increase the translation of animal and clinical studies.