Joachim Schultze | Rheinische Friedrich-Wilhelms-Universität Bonn (original) (raw)

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Papers by Joachim Schultze

Research paper thumbnail of Regulatory T cells: timing is everything

Research paper thumbnail of The detection of minimal residual disease: implications for bone marrow transplantation

Cancer Treatment and Research, Feb 1, 1997

Research paper thumbnail of Gut microbial translocation corrupts myeloid cell function to control bacterial infection during liver cirrhosis

Gut, 2016

Patients with liver cirrhosis suffer from increased susceptibility to life-threatening bacterial ... more Patients with liver cirrhosis suffer from increased susceptibility to life-threatening bacterial infections that cause substantial morbidity. Experimental liver fibrosis in mice induced by bile duct ligation or CCl4 application was used to characterise the mechanisms determining failure of innate immunity to control bacterial infections. In murine liver fibrosis, translocation of gut microbiota induced tonic type I interferon (IFN) expression in the liver. Such tonic IFN expression conditioned liver myeloid cells to produce high concentrations of IFN upon intracellular infection with Listeria that activate cytosolic pattern recognition receptors. Such IFN-receptor signalling caused myeloid cell interleukin (IL)-10 production that corrupted antibacterial immunity, leading to loss of infection-control and to infection-associated mortality. In patients with liver cirrhosis, we also found a prominent liver IFN signature and myeloid cells showed increased IL-10 production after bacterial infection. Thus, myeloid cells are both source and target of IFN-induced and IL-10-mediated immune dysfunction. Antibody-mediated blockade of IFN-receptor or IL-10-receptor signalling reconstituted antibacterial immunity and prevented infection-associated mortality in mice with liver fibrosis. In severe liver fibrosis and cirrhosis, failure to control bacterial infection is caused by augmented IFN and IL-10 expression that incapacitates antibacterial immunity of myeloid cells. Targeted interference with the immune regulatory host factors IL-10 and IFN reconstitutes antibacterial immunity and may be used as therapeutic strategy to control bacterial infections in patients with liver cirrhosis.

Research paper thumbnail of Transcriptome‐based profiling of yolk sac‐derived macrophages reveals a role for Irf8 in macrophage maturation

The EMBO Journal, 2016

Recent studies have shown that tissue macrophages (MΦ) arise from embryonic progenitors of the yo... more Recent studies have shown that tissue macrophages (MΦ) arise from embryonic progenitors of the yolk sac (YS) and fetal liver and colonize tissues before birth. Further studies have proposed that developmentally distinct tissue MΦ can be identified based on the differential expression of F4/80 and CD11b, but whether a characteristic transcriptional profile exists is largely unknown. Here, we took advantage of an inducible fate-mapping system that facilitated the identification of CD45(+)c-kit(-)CX3CR1(+)F4/80(+) (A2) progenitors of the YS as the source of F4/80(hi) but not CD11b(hi) MΦ. Large-scale transcriptional profiling of MΦ precursors from the YS stage to adulthood allowed for building computational models for F4/80(hi) tissue macrophages being direct descendants of A2 progenitors. We further identified a distinct molecular signature of F4/80(hi) and CD11b(hi) MΦ and found that Irf8 was vital for MΦ maturation. Our data provide new cellular and molecular insights into the origin and developmental pathways of tissue MΦ.

Research paper thumbnail of Molecular analysis of acute myeloid leukemia

Research paper thumbnail of Human glioblastoma-associated microglia/monocytes express a distinct RNA profile compared to human control and murine samples

Glia, 2016

Glioblastoma (GBM) is the most aggressive brain tumor in adults. It is strongly infiltrated by mi... more Glioblastoma (GBM) is the most aggressive brain tumor in adults. It is strongly infiltrated by microglia and peripheral monocytes that support tumor growth. In the present study we used RNA sequencing to compare the expression profile of CD11b(+) human glioblastoma-associated microglia/monocytes (hGAMs) to CD11b(+) microglia isolated from non-tumor samples. Hierarchical clustering and principal component analysis showed a clear separation of the two sample groups and we identified 334 significantly regulated genes in hGAMs. In comparison to human control microglia hGAMs upregulated genes associated with mitotic cell cycle, cell migration, cell adhesion, and extracellular matrix organization. We validated the expression of several genes associated with extracellular matrix organization in samples of human control microglia, hGAMs, and the hGAMs-depleted fraction via qPCR. The comparison to murine GAMs (mGAMs) showed that both cell populations share a significant fraction of upregulat...

Research paper thumbnail of TNFa-Blocker: Ursache schwerer Nebenwirkungen gekl�rt

Research paper thumbnail of Markers of Regulatory T Cell Activation

Research paper thumbnail of Marker genes for regulatory T cells from human blood

Research paper thumbnail of Imbalance of DNA-dependent protein kinase subunits in polycythemia vera peripheral blood stem cells

International Journal of Cancer, Feb 1, 2009

Research paper thumbnail of New Antigens and Avenues to Immunotherapy of Cancer

Research paper thumbnail of Balancing intestinal and systemic inflammation through cell type-specific expression of the aryl hydrocarbon receptor repressor

Scientific reports, 2016

As a sensor of polyaromatic chemicals the aryl hydrocarbon receptor (AhR) exerts an important rol... more As a sensor of polyaromatic chemicals the aryl hydrocarbon receptor (AhR) exerts an important role in immune regulation besides its requirement for xenobiotic metabolism. Transcriptional activation of AhR target genes is counterregulated by the AhR repressor (AhRR) but the exact function of the AhRR in vivo is currently unknown. We here show that the AhRR is predominantly expressed in immune cells of the skin and intestine, different from other AhR target genes. Whereas AhRR antagonizes the anti-inflammatory function of the AhR in the context of systemic endotoxin shock, AhR and AhRR act in concert to dampen intestinal inflammation. Specifically, AhRR contributes to the maintenance of colonic intraepithelial lymphocytes and prevents excessive IL-1β production and Th17/Tc17 differentiation. In contrast, the AhRR enhances IFN-γ-production by effector T cells in the inflamed gut. Our findings highlight the physiologic importance of cell-type specific balancing of AhR/AhRR expression in...

Research paper thumbnail of Cancer immunotherapy and diagnosis using cytochrome P450 1B1

Research paper thumbnail of T-cell analysis in identical twins reveals an impaired anti-follicular lymphoma immune response in the patient but not in the healthy twin

British Journal of Haematology, 2002

Research paper thumbnail of Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming

Science translational medicine, Jan 6, 2016

Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol concentrations. D... more Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol concentrations. Despite ongoing advances in the prevention and treatment of atherosclerosis, cardiovascular disease remains the leading cause of death worldwide. Continuous retention of apolipoprotein B-containing lipoproteins in the subendothelial space causes a local overabundance of free cholesterol. Because cholesterol accumulation and deposition of cholesterol crystals (CCs) trigger a complex inflammatory response, we tested the efficacy of the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (CD), a compound that increases cholesterol solubility in preventing and reversing atherosclerosis. We showed that CD treatment of murine atherosclerosis reduced atherosclerotic plaque size and CC load and promoted plaque regression even with a continued cholesterol-rich diet. Mechanistically, CD increased oxysterol production in both macrophages and human atherosclerotic plaques and promoted liver X recep...

Research paper thumbnail of T-Cell-Mediated Immunity against B-Cell Malignancies: Preclinical Results and Translation into a Novel Immunotherapeutic Approach for B-Cell Malignancies

Research paper thumbnail of Characterization of inflammatory markers and transcriptome profiles of differentially activated embryonic stem cell-derived microglia

Glia, Jan 9, 2016

Microglia, the immune cells of the CNS, are highly adaptive cells that can acquire different pro-... more Microglia, the immune cells of the CNS, are highly adaptive cells that can acquire different pro- and anti-inflammatory activation states with distinct functions in CNS homeostasis and pathologies. To study microglial function in vitro, primary microglia or immortalized cell lines are commonly used. An alternative to these cells are embryonic stem cell-derived microglia (ESdM). ESdM have previously been shown to be very similar to primary microglia in terms of expression profiles and surface molecules. In this study, ESdM and primary microglia were treated with different inflammatory stimulants to analyze their ability to adopt different activation states. Using quantitative real-time PCR, comparative transcriptomics, ELISA, and flow cytometry, we found that different activation states can be induced in ESdM, which are similar to those found in primary microglia. These states are characterized by specific sets of inflammatory marker molecules and differential transcriptome signature...

Research paper thumbnail of Conversion of Human Fibroblasts to Stably Self-Renewing Neural Stem Cells with a Single Zinc-Finger Transcription Factor

Stem Cell Reports, 2016

Direct conversion of somatic cells into neural stem cells (NSCs) by defined factors holds great p... more Direct conversion of somatic cells into neural stem cells (NSCs) by defined factors holds great promise for mechanistic studies, drug screening, and potential cell therapies for different neurodegenerative diseases. Here, we report that a single zinc-finger transcription factor, Zfp521, is sufficient for direct conversion of human fibroblasts into long-term self-renewable and multipotent NSCs. In vitro, Zfp521-induced NSCs maintained their characteristics in the absence of exogenous factor expression and exhibited morphological, molecular, developmental, and functional properties that were similar to control NSCs. In addition, the single-seeded induced NSCs were able to form NSC colonies with efficiency comparable with control NSCs and expressed NSC markers. The converted cells were capable of surviving, migrating, and attaining neural phenotypes after transplantation into neonatal mouse and adult rat brains, without forming tumors. Moreover, the Zfp521-induced NSCs predominantly expressed rostral genes. Our results suggest a facilitated approach for establishing human NSCs through Zfp521-driven conversion of fibroblasts.

Research paper thumbnail of In Patients with Multiple Myeloma

Research paper thumbnail of Tumor-necrosis factor impairs CD4+ T cell–mediated immunological control in chronic viral infection

Nature Immunology, 2016

Persistent viral infections are characterized by the simultaneous presence of chronic inflammatio... more Persistent viral infections are characterized by the simultaneous presence of chronic inflammation and T cell dysfunction. In prototypic models of chronicity-infection with human immunodeficiency virus (HIV) or lymphocytic choriomeningitis virus (LCMV)-we used transcriptome-based modeling to reveal that CD4(+) T cells were co-exposed not only to multiple inhibitory signals but also to tumor-necrosis factor (TNF). Blockade of TNF during chronic infection with LCMV abrogated the inhibitory gene-expression signature in CD4(+) T cells, including reduced expression of the inhibitory receptor PD-1, and reconstituted virus-specific immunity, which led to control of infection. Preventing signaling via the TNF receptor selectively in T cells sufficed to induce these effects. Targeted immunological interventions to disrupt the TNF-mediated link between chronic inflammation and T cell dysfunction might therefore lead to therapies to overcome persistent viral infection.

Research paper thumbnail of Regulatory T cells: timing is everything

Research paper thumbnail of The detection of minimal residual disease: implications for bone marrow transplantation

Cancer Treatment and Research, Feb 1, 1997

Research paper thumbnail of Gut microbial translocation corrupts myeloid cell function to control bacterial infection during liver cirrhosis

Gut, 2016

Patients with liver cirrhosis suffer from increased susceptibility to life-threatening bacterial ... more Patients with liver cirrhosis suffer from increased susceptibility to life-threatening bacterial infections that cause substantial morbidity. Experimental liver fibrosis in mice induced by bile duct ligation or CCl4 application was used to characterise the mechanisms determining failure of innate immunity to control bacterial infections. In murine liver fibrosis, translocation of gut microbiota induced tonic type I interferon (IFN) expression in the liver. Such tonic IFN expression conditioned liver myeloid cells to produce high concentrations of IFN upon intracellular infection with Listeria that activate cytosolic pattern recognition receptors. Such IFN-receptor signalling caused myeloid cell interleukin (IL)-10 production that corrupted antibacterial immunity, leading to loss of infection-control and to infection-associated mortality. In patients with liver cirrhosis, we also found a prominent liver IFN signature and myeloid cells showed increased IL-10 production after bacterial infection. Thus, myeloid cells are both source and target of IFN-induced and IL-10-mediated immune dysfunction. Antibody-mediated blockade of IFN-receptor or IL-10-receptor signalling reconstituted antibacterial immunity and prevented infection-associated mortality in mice with liver fibrosis. In severe liver fibrosis and cirrhosis, failure to control bacterial infection is caused by augmented IFN and IL-10 expression that incapacitates antibacterial immunity of myeloid cells. Targeted interference with the immune regulatory host factors IL-10 and IFN reconstitutes antibacterial immunity and may be used as therapeutic strategy to control bacterial infections in patients with liver cirrhosis.

Research paper thumbnail of Transcriptome‐based profiling of yolk sac‐derived macrophages reveals a role for Irf8 in macrophage maturation

The EMBO Journal, 2016

Recent studies have shown that tissue macrophages (MΦ) arise from embryonic progenitors of the yo... more Recent studies have shown that tissue macrophages (MΦ) arise from embryonic progenitors of the yolk sac (YS) and fetal liver and colonize tissues before birth. Further studies have proposed that developmentally distinct tissue MΦ can be identified based on the differential expression of F4/80 and CD11b, but whether a characteristic transcriptional profile exists is largely unknown. Here, we took advantage of an inducible fate-mapping system that facilitated the identification of CD45(+)c-kit(-)CX3CR1(+)F4/80(+) (A2) progenitors of the YS as the source of F4/80(hi) but not CD11b(hi) MΦ. Large-scale transcriptional profiling of MΦ precursors from the YS stage to adulthood allowed for building computational models for F4/80(hi) tissue macrophages being direct descendants of A2 progenitors. We further identified a distinct molecular signature of F4/80(hi) and CD11b(hi) MΦ and found that Irf8 was vital for MΦ maturation. Our data provide new cellular and molecular insights into the origin and developmental pathways of tissue MΦ.

Research paper thumbnail of Molecular analysis of acute myeloid leukemia

Research paper thumbnail of Human glioblastoma-associated microglia/monocytes express a distinct RNA profile compared to human control and murine samples

Glia, 2016

Glioblastoma (GBM) is the most aggressive brain tumor in adults. It is strongly infiltrated by mi... more Glioblastoma (GBM) is the most aggressive brain tumor in adults. It is strongly infiltrated by microglia and peripheral monocytes that support tumor growth. In the present study we used RNA sequencing to compare the expression profile of CD11b(+) human glioblastoma-associated microglia/monocytes (hGAMs) to CD11b(+) microglia isolated from non-tumor samples. Hierarchical clustering and principal component analysis showed a clear separation of the two sample groups and we identified 334 significantly regulated genes in hGAMs. In comparison to human control microglia hGAMs upregulated genes associated with mitotic cell cycle, cell migration, cell adhesion, and extracellular matrix organization. We validated the expression of several genes associated with extracellular matrix organization in samples of human control microglia, hGAMs, and the hGAMs-depleted fraction via qPCR. The comparison to murine GAMs (mGAMs) showed that both cell populations share a significant fraction of upregulat...

Research paper thumbnail of TNFa-Blocker: Ursache schwerer Nebenwirkungen gekl�rt

Research paper thumbnail of Markers of Regulatory T Cell Activation

Research paper thumbnail of Marker genes for regulatory T cells from human blood

Research paper thumbnail of Imbalance of DNA-dependent protein kinase subunits in polycythemia vera peripheral blood stem cells

International Journal of Cancer, Feb 1, 2009

Research paper thumbnail of New Antigens and Avenues to Immunotherapy of Cancer

Research paper thumbnail of Balancing intestinal and systemic inflammation through cell type-specific expression of the aryl hydrocarbon receptor repressor

Scientific reports, 2016

As a sensor of polyaromatic chemicals the aryl hydrocarbon receptor (AhR) exerts an important rol... more As a sensor of polyaromatic chemicals the aryl hydrocarbon receptor (AhR) exerts an important role in immune regulation besides its requirement for xenobiotic metabolism. Transcriptional activation of AhR target genes is counterregulated by the AhR repressor (AhRR) but the exact function of the AhRR in vivo is currently unknown. We here show that the AhRR is predominantly expressed in immune cells of the skin and intestine, different from other AhR target genes. Whereas AhRR antagonizes the anti-inflammatory function of the AhR in the context of systemic endotoxin shock, AhR and AhRR act in concert to dampen intestinal inflammation. Specifically, AhRR contributes to the maintenance of colonic intraepithelial lymphocytes and prevents excessive IL-1β production and Th17/Tc17 differentiation. In contrast, the AhRR enhances IFN-γ-production by effector T cells in the inflamed gut. Our findings highlight the physiologic importance of cell-type specific balancing of AhR/AhRR expression in...

Research paper thumbnail of Cancer immunotherapy and diagnosis using cytochrome P450 1B1

Research paper thumbnail of T-cell analysis in identical twins reveals an impaired anti-follicular lymphoma immune response in the patient but not in the healthy twin

British Journal of Haematology, 2002

Research paper thumbnail of Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming

Science translational medicine, Jan 6, 2016

Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol concentrations. D... more Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol concentrations. Despite ongoing advances in the prevention and treatment of atherosclerosis, cardiovascular disease remains the leading cause of death worldwide. Continuous retention of apolipoprotein B-containing lipoproteins in the subendothelial space causes a local overabundance of free cholesterol. Because cholesterol accumulation and deposition of cholesterol crystals (CCs) trigger a complex inflammatory response, we tested the efficacy of the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (CD), a compound that increases cholesterol solubility in preventing and reversing atherosclerosis. We showed that CD treatment of murine atherosclerosis reduced atherosclerotic plaque size and CC load and promoted plaque regression even with a continued cholesterol-rich diet. Mechanistically, CD increased oxysterol production in both macrophages and human atherosclerotic plaques and promoted liver X recep...

Research paper thumbnail of T-Cell-Mediated Immunity against B-Cell Malignancies: Preclinical Results and Translation into a Novel Immunotherapeutic Approach for B-Cell Malignancies

Research paper thumbnail of Characterization of inflammatory markers and transcriptome profiles of differentially activated embryonic stem cell-derived microglia

Glia, Jan 9, 2016

Microglia, the immune cells of the CNS, are highly adaptive cells that can acquire different pro-... more Microglia, the immune cells of the CNS, are highly adaptive cells that can acquire different pro- and anti-inflammatory activation states with distinct functions in CNS homeostasis and pathologies. To study microglial function in vitro, primary microglia or immortalized cell lines are commonly used. An alternative to these cells are embryonic stem cell-derived microglia (ESdM). ESdM have previously been shown to be very similar to primary microglia in terms of expression profiles and surface molecules. In this study, ESdM and primary microglia were treated with different inflammatory stimulants to analyze their ability to adopt different activation states. Using quantitative real-time PCR, comparative transcriptomics, ELISA, and flow cytometry, we found that different activation states can be induced in ESdM, which are similar to those found in primary microglia. These states are characterized by specific sets of inflammatory marker molecules and differential transcriptome signature...

Research paper thumbnail of Conversion of Human Fibroblasts to Stably Self-Renewing Neural Stem Cells with a Single Zinc-Finger Transcription Factor

Stem Cell Reports, 2016

Direct conversion of somatic cells into neural stem cells (NSCs) by defined factors holds great p... more Direct conversion of somatic cells into neural stem cells (NSCs) by defined factors holds great promise for mechanistic studies, drug screening, and potential cell therapies for different neurodegenerative diseases. Here, we report that a single zinc-finger transcription factor, Zfp521, is sufficient for direct conversion of human fibroblasts into long-term self-renewable and multipotent NSCs. In vitro, Zfp521-induced NSCs maintained their characteristics in the absence of exogenous factor expression and exhibited morphological, molecular, developmental, and functional properties that were similar to control NSCs. In addition, the single-seeded induced NSCs were able to form NSC colonies with efficiency comparable with control NSCs and expressed NSC markers. The converted cells were capable of surviving, migrating, and attaining neural phenotypes after transplantation into neonatal mouse and adult rat brains, without forming tumors. Moreover, the Zfp521-induced NSCs predominantly expressed rostral genes. Our results suggest a facilitated approach for establishing human NSCs through Zfp521-driven conversion of fibroblasts.

Research paper thumbnail of In Patients with Multiple Myeloma

Research paper thumbnail of Tumor-necrosis factor impairs CD4+ T cell–mediated immunological control in chronic viral infection

Nature Immunology, 2016

Persistent viral infections are characterized by the simultaneous presence of chronic inflammatio... more Persistent viral infections are characterized by the simultaneous presence of chronic inflammation and T cell dysfunction. In prototypic models of chronicity-infection with human immunodeficiency virus (HIV) or lymphocytic choriomeningitis virus (LCMV)-we used transcriptome-based modeling to reveal that CD4(+) T cells were co-exposed not only to multiple inhibitory signals but also to tumor-necrosis factor (TNF). Blockade of TNF during chronic infection with LCMV abrogated the inhibitory gene-expression signature in CD4(+) T cells, including reduced expression of the inhibitory receptor PD-1, and reconstituted virus-specific immunity, which led to control of infection. Preventing signaling via the TNF receptor selectively in T cells sufficed to induce these effects. Targeted immunological interventions to disrupt the TNF-mediated link between chronic inflammation and T cell dysfunction might therefore lead to therapies to overcome persistent viral infection.