16 results on '"Heide Dierbach"'
Search Results
2. Data from miR-146a Controls Immune Response in the Melanoma Microenvironment
- Author
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Robert Zeiser, Melanie Boerries, Frank Meiss, Annette Schmitt-Graeff, Heide Dierbach, Dietmar Pfeifer, Geoffroy Andrieux, Martina Falk, Dominik Schmidt, Sandra Duquesne, Wolfgang Melchinger, Kathrin Hanke, Hana Andrlova, Natalie Stickel, and Justin Mastroianni
- Abstract
MicroRNAs (miR) are small noncoding RNAs that regulate gene expression, posttranscription, and manipulate immune responses in different types of cancers. In this study, we identify miR-146a as a negative regulator of immune activation, comparable to immune-checkpoint molecules. miR-146a levels were increased in melanoma microenvironmental tissue, and miR-146a−/− mice survived longer and developed less metastases in comparison with wild-type melanoma-bearing mice. T cells isolated from miR-146a−/− mice revealed higher expression levels of the miR-146a target gene Stat1 and the Stat1-regulated cytokine IFNγ. Neutralization of IFNγ in miR-146a−/− mice decreased survival and increased melanoma metastasis patterns to those of wild-type mice. In vitro, IFNγ reduced melanoma cell migration, cell-cycle activity, and basal metabolic rate. Conversely, IFNγ also increased PD-L1 levels on the melanoma cells, which may counterbalance some of the beneficial effects increasing immune escape in vivo. Combined treatment with a miR-146a antagomiR and anti–PD-1 resulted in improved survival over isotype control or anti–PD-1 treatment alone. In summary, these data show that miR-146a plays a central role within the STAT1/IFNγ axis in the melanoma microenvironment, affecting melanoma migration, proliferation, and mitochondrial fitness as well as PD-L1 levels. Additionally, combined inhibition of PD-1 and miR-146a could be a novel strategy to enhance antitumor immune response elicited by checkpoint therapy.Significance:These findings identify a microRNA–based mechanism by which melanoma cells escape the immune system, providing a new therapeutic strategy to improve the current management of patients with melanoma.
- Published
- 2023
3. miR-146a Controls Immune Response in the Melanoma Microenvironment
- Author
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Heide Dierbach, Justin Mastroianni, Annette Schmitt-Graeff, Martina Falk, Natalie Stickel, Dietmar Pfeifer, Melanie Boerries, Kathrin Hanke, Wolfgang Melchinger, Sandra Duquesne, Dominik Schmidt, Frank Meiss, Hana Andrlová, Geoffroy Andrieux, and Robert Zeiser
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_treatment ,Biology ,B7-H1 Antigen ,Article ,Interferon-gamma ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Cell Movement ,Interferon ,Tumor Cells, Cultured ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Interferon gamma ,Melanoma ,Skin ,Mice, Knockout ,Regulation of gene expression ,Cell migration ,Cell cycle ,Prognosis ,medicine.disease ,3. Good health ,Gene Expression Regulation, Neoplastic ,Mice, Inbred C57BL ,MicroRNAs ,STAT1 Transcription Factor ,030104 developmental biology ,Cytokine ,Oncology ,Case-Control Studies ,030220 oncology & carcinogenesis ,Cancer research ,medicine.drug - Abstract
MicroRNAs (miR) are small noncoding RNAs that regulate gene expression, posttranscription, and manipulate immune responses in different types of cancers. In this study, we identify miR-146a as a negative regulator of immune activation, comparable to immune-checkpoint molecules. miR-146a levels were increased in melanoma microenvironmental tissue, and miR-146a−/− mice survived longer and developed less metastases in comparison with wild-type melanoma-bearing mice. T cells isolated from miR-146a−/− mice revealed higher expression levels of the miR-146a target gene Stat1 and the Stat1-regulated cytokine IFNγ. Neutralization of IFNγ in miR-146a−/− mice decreased survival and increased melanoma metastasis patterns to those of wild-type mice. In vitro, IFNγ reduced melanoma cell migration, cell-cycle activity, and basal metabolic rate. Conversely, IFNγ also increased PD-L1 levels on the melanoma cells, which may counterbalance some of the beneficial effects increasing immune escape in vivo. Combined treatment with a miR-146a antagomiR and anti–PD-1 resulted in improved survival over isotype control or anti–PD-1 treatment alone. In summary, these data show that miR-146a plays a central role within the STAT1/IFNγ axis in the melanoma microenvironment, affecting melanoma migration, proliferation, and mitochondrial fitness as well as PD-L1 levels. Additionally, combined inhibition of PD-1 and miR-146a could be a novel strategy to enhance antitumor immune response elicited by checkpoint therapy. Significance: These findings identify a microRNA–based mechanism by which melanoma cells escape the immune system, providing a new therapeutic strategy to improve the current management of patients with melanoma.
- Published
- 2019
4. Neutrophils provide cellular communication between ileum and mesenteric lymph nodes at graft-versus-host disease onset
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Zhan Gao, Jan Hülsdünker, Katja J. Ottmüller, Sandra Duquesne, Geoffrey R. Hill, Oliver S. Thomas, Hannes P. Neeff, Brian T. Fife, Marie Follo, Robert Zeiser, Heide Dierbach, Bruce R. Blazar, Georg Häcker, Gabriele Prinz, Motoko Koyama, Andreas Beilhack, Ali Al-Ahmad, Tim Lämmermann, Susanne Kirschnek, and Martin J. Blaser
- Subjects
0301 basic medicine ,Neutrophils ,T cell ,Immunology ,Graft vs Host Disease ,chemical and pharmacologic phenomena ,Cell Communication ,Major histocompatibility complex ,Biochemistry ,Pathogenesis ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Ileum ,medicine ,Animals ,Mesenteric lymph nodes ,Mesentery ,Protein Kinase Inhibitors ,Mice, Knockout ,Mice, Inbred BALB C ,Innate immune system ,biology ,business.industry ,Janus Kinase 1 ,Cell Biology ,Hematology ,Janus Kinase 2 ,medicine.disease ,030104 developmental biology ,Graft-versus-host disease ,medicine.anatomical_structure ,Neutrophil Infiltration ,Acute Disease ,biology.protein ,Lymph Nodes ,Cell activation ,business ,030215 immunology - Abstract
Conditioning-induced damage of the intestinal tract plays a critical role during the onset of acute graft-versus-host disease (GVHD). Therapeutic interference with these early events of GVHD is difficult, and currently used immunosuppressive drugs mainly target donor T cells. However, not donor T cells but neutrophils reach the sites of tissue injury first, and therefore could be a potential target for GVHD prevention. A detailed analysis of neutrophil fate during acute GVHD and the effect on T cells is difficult because of the short lifespan of this cell type. By using a novel photoconverter reporter system, we show that neutrophils that had been photoconverted in the ileum postconditioning later migrated to mesenteric lymph nodes (mLN). This neutrophil migration was dependent on the intestinal microflora. In the mLN, neutrophils colocalized with T cells and presented antigen on major histocompatibility complex (MHC)-II, thereby affecting T cell expansion. Pharmacological JAK1/JAK2 inhibition reduced neutrophil influx into the mLN and MHC-II expression, thereby interfering with an early event in acute GVHD pathogenesis. In agreement with this finding, neutrophil depletion reduced acute GVHD. We conclude that neutrophils are attracted to the ileum, where the intestinal barrier is disrupted, and then migrate to the mLN, where they participate in alloantigen presentation. JAK1/JAK2-inhibition can interfere with this process, which provides a potential therapeutic strategy to prevent early events of tissue damage-related innate immune cell activation and, ultimately, GVHD.
- Published
- 2018
5. Biglycan expression in the melanoma microenvironment promotes invasiveness via increased tissue stiffness inducing integrin-β1 expression
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Andreas Narr, Josef Madl, Susana Minguet, Melanie Boerries, Paul Timpson, Kristin Technau-Hafsi, Cristina Has, Winfried Römer, Justin Mastroianni, Robert Zeiser, Marco Idzko, Hauke Busch, Annette Schmitt-Graeff, Venugopal Rao Mittapalli, Claire Vennin, Heide Dierbach, Florian Wernet, Wolfgang Melchinger, Johannes S. Kern, Gabriele Ihorst, Ricarda Herr, Hendrik Ungefroren, Justus Duyster, Tilman Brummer, Hana Andrlová, Marie Follo, and Frank Meiss
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Male ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Pathology ,Integrin β1 ,Melanoma, Experimental ,integrin-β1 ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Internal medicine ,Biglycan ,Cancer centre ,Tumor Microenvironment ,melanoma ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,In patient ,tissue stiffness ,Mice, Knockout ,business.industry ,Integrin beta1 ,Melanoma ,Cancer ,Fibroblasts ,Prognosis ,medicine.disease ,Survival Analysis ,microenvironment ,3. Good health ,Gene Expression Regulation, Neoplastic ,Disease Models, Animal ,030104 developmental biology ,030220 oncology & carcinogenesis ,Heterografts ,Female ,Human melanoma ,Tissue stiffness ,business ,Biomarkers ,Research Paper - Abstract
// Hana Andrlova 1 , Justin Mastroianni 1 , Josef Madl 2, 3 , Johannes S. Kern 4 , Wolfgang Melchinger 1 , Heide Dierbach 1 , Florian Wernet 1 , Marie Follo 1 , Kristin Technau-Hafsi 4 , Cristina Has 4 , Venugopal Rao Mittapalli 4 , Marco Idzko 5 , Ricarda Herr 6 , Tilman Brummer 6 , Hendrik Ungefroren 7 , Hauke Busch 7, 8, 9, 15 , Melanie Boerries 6, 8, 15 , Andreas Narr 10, 11 , Gabriele Ihorst 12 , Claire Vennin 13 , Annette Schmitt-Graeff 14 , Susana Minguet 10, 11 , Paul Timpson 13 , Justus Duyster 1 , Frank Meiss 4 , Winfried Romer 2, 3 and Robert Zeiser 1, 3 1 Department of Hematology and Oncology, University Medical Center, Faculty of Medicine, Freiburg, Germany 2 Faculty of Biology, Albert Ludwigs University, Freiburg, Germany 3 BIOSS Centre for Biological Signalling Studies, Albert Ludwigs University Freiburg, Freiburg, Germany 4 Department of Dermatology and Venereology, University Medical Center, Freiburg, Germany 5 Department of Pneumology, University Medical Center, Freiburg, Germany 6 Institut fur Molekulare Medizin und Zellforschung, University Medical Center, Freiburg, Germany 7 First Department of Medicine, University of Lubeck, Lubeck, Germany 8 German Cancer Consortium (DKTK), Freiburg, Germany 9 Institute of Experimental Dermatology, University of Lubeck, Lubeck, Germany 10 Department of Immunology, BIOSS Center for Biological Signaling Studies, Faculty of Biology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany 11 Center of Chronic Immunodeficiency CCI, University Clinics and Medical Faculty, Freiburg, Germany 12 Clinical Trials Unit, University Medical Center, Freiburg, Germany 13 The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Sydney, Australia 14 Department of Pathology, University Medical Center, Faculty of Medicine, Freiburg, Germany 15 German Cancer Research Center (DKFZ), Heidelberg, Germany Correspondence to: Robert Zeiser, email: robert.zeiser@uniklinik-freiburg.de Keywords: biglycan, melanoma, microenvironment, tissue stiffness, integrin-β1 Received: October 04, 2016 Accepted: March 14, 2017 Published: April 17, 2017 ABSTRACT Novel targeted and immunotherapeutic approaches have revolutionized the treatment of metastatic melanoma. A better understanding of the melanoma-microenvironment, in particular the interaction of cells with extracellular matrix molecules, may help to further improve these new therapeutic strategies. We observed that the extracellular matrix molecule biglycan (Bgn) was expressed in certain human melanoma cells and primary fibroblasts when evaluated by microarray-based gene expression analysis. Bgn expression in the melanoma tissues correlated with low overall-survival and low progression-free-survival in patients. To understand the functional role of Bgn we used gene-targeted mice lacking functional Bgn. Here we observed that melanoma growth, metastasis-formation and tumor-related death were reduced in Bgn -/- mice compared to Bgn +/+ mice. In vitro invasion of melanoma cells into organotypic-matrices derived from Bgn -/- fibroblasts was reduced compared to melanoma invasion into Bgn -proficient matrices. Tissue stiffness as determined by atomic-force-microscopy was reduced in Bgn -/- matrices. Isolation of melanoma cells and fibroblasts from the stiffer Bgn +/+ matrices revealed an increase in integrin-β1 expression compared to the Bgn -/- fibroblast matrices. Overexpression of integrin-β1 in B16-melanoma cells abolished the survival benefit seen in Bgn -/- mice. Consistent with the studies performed in mice, the abundance of Bgn-expression in human melanoma samples positively correlated with the expression of integrin-β1, which is in agreement with results from the organotypic invasion-assay and the in vivo mouse studies. This study describes a novel role for Bgn-related tissue stiffness in the melanoma-microenvironment via regulation of integrin-β1 expression by melanoma cells in both mice and humans.
- Published
- 2017
6. Metadherin exon 11 skipping variant enhances metastatic spread of ovarian cancer
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Heide Dierbach, Annette Hasenburg, Sebastian Halbach, Marie Follo, Stefan Haug, Martin Köhler, Tilman Brummer, Martin Werner, Verónica I. Dumit, Joern Dengjel, Amelie Proske, Silke Laßmann, Justin Mastroianni, Robert Zeiser, Ralph Wäsch, Sebastian Herzog, and Dominik Schnerch
- Subjects
Cancer Research ,Gene knockdown ,endocrine system diseases ,Cell adhesion molecule ,Wild type ,MTDH ,Biology ,medicine.disease ,female genital diseases and pregnancy complications ,Exon ,Oncology ,Membrane protein ,Gene Knockdown Techniques ,Cancer research ,medicine ,Ovarian cancer - Abstract
Metastatic ovarian cancer has a dismal prognosis and current chemotherapeutic approaches have very limited success. Metadherin (MTDH) is expressed in human ovarian cancer tissue and its expression inversely correlates with patients overall survival. Consistent with these studies, we observed MTDH expression in tissue specimens of FIGO Stage III ovarian carcinomas (72/83 cases). However, we also observed this in normal human ovarian epithelial (OE) cells, which raised the question of whether MTDH-variants with functional differences exist. We identified a novel MTDH exon 11 skipping variant (MTDHdel) which was seen at higher levels in ovarian cancer compared to benign OE cells. We analyzed MTDH-binding partner interactions and found that 12 members of the small ribosomal subunit and several mRNA binding proteins bound stronger to MTDHdel than to wildtype MTDH which indicates differential effects on gene translation. Knockdown of MTDH in ovarian cancer cells reduced the amount of distant metastases and improved the survival of ovarian cancer-bearing mice. Selective overexpression of the MTDHdel enhanced murine and human ovarian cancer progression and caused a malignant phenotype in originally benign human OE cells. MTDHdel was detectable in microdissected ovarian cancer cells of some human tissue specimens of ovarian carcinomas. In summary, we have identified a novel MTDH exon 11 skipping variant that shows enhanced binding to small ribosomal subunit members and that caused reduced overall survival of ovarian cancer bearing mice. Based on the findings in the murine system and in human tissues, MTDHdel must be considered a major promalignant factor for ovarian cancer.
- Published
- 2014
7. Inflammatory neovascularization during graft-versus-host disease is regulated by αv integrin and miR-100
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Martin Béhé, Franziska Bluhm, Franziska Leonhardt, Sebastian Grundmann, Annette Schmitt-Gräff, Wolfgang Weber, Robert Zeiser, Katarina Riesner, Heide Dierbach, Gabriele Prinz, Rebecca A. Dumont, Friederike Braun, Anne-Kathrin Hechinger, Jürgen Finke, Melpomeni Fani, Ulrike V. Gerlach, and Olaf Penack
- Subjects
Male ,genetic structures ,Blotting, Western ,Immunology ,Integrin ,Ischemia ,Graft vs Host Disease ,Real-Time Polymerase Chain Reaction ,Biochemistry ,Flow cytometry ,Immunoenzyme Techniques ,Neovascularization ,Mice ,Immune system ,immune system diseases ,medicine ,Animals ,Humans ,RNA, Messenger ,Bone Marrow Transplantation ,Inflammation ,Mice, Inbred BALB C ,Neovascularization, Pathologic ,medicine.diagnostic_test ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,business.industry ,Cell Biology ,Hematology ,Integrin alphaV ,Flow Cytometry ,medicine.disease ,eye diseases ,Pathophysiology ,Mice, Inbred C57BL ,Intestinal Diseases ,MicroRNAs ,surgical procedures, operative ,Real-time polymerase chain reaction ,Graft-versus-host disease ,Positron-Emission Tomography ,Luminescent Measurements ,biology.protein ,Female ,sense organs ,medicine.symptom ,business - Abstract
Acute graft-versus-host disease (GvHD) is a complex process involving endothelial damage and neovascularization. Better understanding of the pathophysiology of neovascularization during GvHD could help to target this process while leaving T-cell function intact. Under ischemic conditions, neovascularization is regulated by different micro RNAs (miRs), which potentially play a role in inflamed hypoxic GvHD target organs. We observed strong neovascularization in the murine inflamed intestinal tract (IT) during GvHD. Positron emission tomography imaging demonstrated abundant αvβ3 integrin expression within intestinal neovascularization areas. To interfere with neovascularization, we targeted αv integrin-expressing endothelial cells, which blocked their accumulation in the IT and reduced GvHD severity independent of immune reconstitution and graft-versus-tumor effects. Additionally, enhanced neovascularization and αv integrin expression correlated with GvHD severity in humans. Expression analysis of miRs in the inflamed IT of mice developing GvHD identified miR-100 as significantly downregulated. Inactivation of miR-100 enhanced GvHD indicating a protective role for miR-100 via blocking inflammatory neovascularization. Our data from the mouse model and patients indicate that inflammatory neovascularization is a central event during intestinal GvHD that can be inhibited by targeting αv integrin. We identify negative regulation of GvHD-related neovascularization by miR-100, which indicates common pathomechanistic features of GvHD and ischemia.
- Published
- 2013
8. Neutrophil Granulocytes Mediate Cellular Communication Between the Damaged Intestinal Tract and Mesenteric Lymph Nodes at the Onset of Intestinal Graft-Versus-Host Disease
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Jan Hülsdünker, Andreas Beilhack, Heide Dierbach, Georg Häcker, Gabriele Prinz, Marie Follo, Robert Zeiser, Susanne Kirschnek, and Katja J. Ottmüller
- Subjects
Transplantation ,medicine.anatomical_structure ,business.industry ,Immunology ,Medicine ,Mesenteric lymph nodes ,Intestinal Graft Versus Host Disease ,Hematology ,business - Published
- 2016
- Full Text
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9. A Novel Function for P2Y2 in Myeloid Recipient-Derived Cells during Graft-versus-Host Disease
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Korcan Ayata, Petya Apostolova, Verena Klämbt, Lukas Schwab, Marco Prinz, Jan Hülsdünker, Annette Schmitt-Graeff, Robert Zeiser, Heide Dierbach, Gabriele Prinz, Marco Idzko, Marie Follo, and Sebastian A. Wohlfeil
- Subjects
Myeloid ,MAP Kinase Signaling System ,medicine.medical_treatment ,Immunology ,Graft vs Host Disease ,chemical and pharmacologic phenomena ,Hematopoietic stem cell transplantation ,Receptors, Purinergic P2Y2 ,Mice ,Adenosine Triphosphate ,immune system diseases ,medicine ,Immunology and Allergy ,Animals ,Humans ,Myeloid Cells ,Molecular Targeted Therapy ,Receptor ,Interleukin 6 ,Mice, Knockout ,Innate immune system ,biology ,Interleukin-6 ,Hematopoietic Stem Cell Transplantation ,medicine.disease ,Transplantation ,Intestines ,Mice, Inbred C57BL ,surgical procedures, operative ,medicine.anatomical_structure ,Graft-versus-host disease ,Myeloperoxidase ,biology.protein ,Reactive Oxygen Species - Abstract
Acute graft-versus-host disease (GvHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation. During the initiation phase of acute GvHD, endogenous danger signals such as ATP are released and inform the innate immune system via activation of the purinergic receptor P2X7 that a noninfectious damage has occurred. A second ATP-activated purinergic receptor involved in inflammatory diseases is P2Y2. In this study, we used P2y2−/− mice to test the role of this receptor in GvHD. P2y2−/− recipients experienced reduced GvHD-related mortality, IL-6 levels, enterocyte apoptosis, and histopathology scores. Chimeric mice with P2y2 deficiency restricted to hematopoietic tissues survived longer after GvHD induction than did wild-type mice. P2y2 deficiency of the recipient was connected to lower levels of myeloperoxidase in the intestinal tract of mice developing GvHD and a reduced myeloid cell signature. Selective deficiency of P2Y2 in inflammatory monocytes decreased GvHD severity. Mechanistically, P2y2−/− inflammatory monocytes displayed defective ERK activation and reactive oxygen species production. Compatible with a role of P2Y2 in human GvHD, the frequency of P2Y2+ cells in inflamed GvHD lesions correlated with histopathological GvHD severity. Our findings indicate a novel function for P2Y2 in ATP-activated recipient myeloid cells during GvHD, which could be exploited when targeting danger signals to prevent GvHD.
- Published
- 2015
10. The IL-33/ST2 axis augments effector T-cell responses during acute GVHD
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Brent H. Koehn, Tobias Wertheimer, James L.M. Ferrara, Vincent Schwarze, Patricia A. Taylor, Lukas Schwab, Yvonne Beck, Robert Zeiser, Natalie Stickel, Annette Schmitt-Graeff, Max Warncke, Susumu Nakae, Benjamin M. Matta, Dawn K. Reichenbach, Jason Devlin, Victor Tkachev, Marie Follo, Heth R. Turnquist, Bruce R. Blazar, Justus Duyster, Dietmar Pfeifer, Tobias Junt, Elisabeth Lieberknecht, Heide Dierbach, Quan Liu, Gabriele Prinz, and Simon C. Watkins
- Subjects
Isoantigens ,Transplantation Conditioning ,T cell ,T-Lymphocytes ,Immunology ,Interleukin-1 Receptor-Like 1 Protein ,Gene Expression ,Graft vs Host Disease ,chemical and pharmacologic phenomena ,Receptors, Cell Surface ,Biochemistry ,Severity of Illness Index ,Interferon-gamma ,Mice ,Downregulation and upregulation ,immune system diseases ,medicine ,Animals ,Cluster Analysis ,Humans ,Transplantation, Homologous ,Intestinal Mucosa ,Receptor ,Mice, Knockout ,business.industry ,Gene Expression Profiling ,Interleukins ,Hematopoietic Stem Cell Transplantation ,Interleukin ,Cell Biology ,Hematology ,Interleukin-33 ,Tissue Donors ,Transplantation ,Interleukin 33 ,Intestines ,Disease Models, Animal ,surgical procedures, operative ,medicine.anatomical_structure ,Acute Disease ,Cancer research ,Tumor necrosis factor alpha ,business - Abstract
Interleukin (IL)-33 binding to the receptor suppression of tumorigenicity 2 (ST2) produces pro-inflammatory and anti-inflammatory effects. Increased levels of soluble ST2 (sST2) are a biomarker for steroid-refractory graft-versus-host disease (GVHD) and mortality. However, whether sST2 has a role as an immune modulator or only as a biomarker during GVHD was unclear. We show increased IL-33 production by nonhematopoietic cells in the gastrointestinal (GI) tract in mice post-conditioning and patients during GVHD. Exogenous IL-33 administration during the peak inflammatory response worsened GVHD. Conversely, GVHD lethality and tumor necrosis factor-α production was significantly reduced in il33(-/-) recipients. ST2 was upregulated on murine and human alloreactive T cells and sST2 increased as experimental GVHD progressed. Concordantly, st2(-/-) vs wild-type (WT) donor T cells had a marked reduction in GVHD lethality and GI histopathology. Alloantigen-induced IL-18 receptor upregulation was lower in st2(-/-) T cells, and linked to reduced interferon-γ production by st2(-/-) vs WT T cells during GVHD. Blockade of IL-33/ST2 interactions during allogeneic-hematopoietic cell transplantation by exogenous ST2-Fc infusions had a marked reduction in GVHD lethality, indicating a role of ST2 as a decoy receptor modulating GVHD. Together, these studies point to the IL-33/ST2 axis as a novel and potent target for GVHD therapy.
- Published
- 2014
11. Therapeutic activity of multiple common γ-chain cytokine inhibition in acute and chronic GVHD
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Kathrin Hanke, Robert Zeiser, Heide Dierbach, Gabriele Prinz, Anne Kathrin Hechinger, Bruce R. Blazar, Dietmar Pfeifer, Cameron McDonald-Hyman, Jiri Kovarik, Franziska Leonhardt, Patricia A. Taylor, Björn Hackanson, Annette Schmitt-Graeff, Ryan Flynn, and Benjamin A. H. Smith
- Subjects
Granzyme B production ,medicine.medical_treatment ,Immunology ,Blotting, Western ,Fluorescent Antibody Technique ,Graft vs Host Disease ,CD8-Positive T-Lymphocytes ,Biochemistry ,Mice ,immune system diseases ,medicine ,Cytotoxic T cell ,Animals ,Humans ,Interleukin 6 ,Cells, Cultured ,Bone Marrow Transplantation ,Mice, Inbred BALB C ,biology ,business.industry ,Janus kinase 3 ,Interleukin ,Antibodies, Monoclonal ,Janus Kinase 3 ,Cell Biology ,Hematology ,Flow Cytometry ,Mice, Inbred C57BL ,surgical procedures, operative ,Cytokine ,Interleukin 15 ,Acute Disease ,Chronic Disease ,biology.protein ,Cytokines ,Tumor necrosis factor alpha ,Female ,business ,Interleukin Receptor Common gamma Subunit - Abstract
The common γ chain (CD132) is a subunit of the interleukin (IL) receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Because levels of several of these cytokines were shown to be increased in the serum of patients developing acute and chronic graft-versus-host disease (GVHD), we reasoned that inhibition of CD132 could have a profound effect on GVHD. We observed that anti-CD132 monoclonal antibody (mAb) reduced acute GVHD potently with respect to survival, production of tumor necrosis factor, interferon-γ, and IL-6, and GVHD histopathology. Anti-CD132 mAb afforded protection from GVHD partly via inhibition of granzyme B production in CD8 T cells, whereas exposure of CD8 T cells to IL-2, IL-7, IL-15, and IL-21 increased granzyme B production. Also, T cells exposed to anti-CD132 mAb displayed a more naive phenotype in microarray-based analyses and showed reduced Janus kinase 3 (JAK3) phosphorylation upon activation. Consistent with a role of JAK3 in GVHD, Jak3(-/-) T cells caused less severe GVHD. Additionally, anti-CD132 mAb treatment of established chronic GVHD reversed liver and lung fibrosis, and pulmonary dysfunction characteristic of bronchiolitis obliterans. We conclude that acute GVHD and chronic GVHD, caused by T cells activated by common γ-chain cytokines, each represent therapeutic targets for anti-CD132 mAb immunomodulation.
- Published
- 2014
12. Metadherin exon 11 skipping variant enhances metastatic spread of ovarian cancer
- Author
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Stefan, Haug, Dominik, Schnerch, Sebastian, Halbach, Justin, Mastroianni, Verónica I, Dumit, Marie, Follo, Annette, Hasenburg, Martin, Köhler, Heide, Dierbach, Sebastian, Herzog, Amelie, Proske, Martin, Werner, Joern, Dengjel, Tilman, Brummer, Silke, Laßmann, Ralph, Wäsch, and Robert, Zeiser
- Subjects
Ovarian Neoplasms ,Membrane Proteins ,RNA-Binding Proteins ,Exons ,Mice, Inbred C57BL ,Mice ,Cell Line, Tumor ,Gene Knockdown Techniques ,Animals ,Humans ,Female ,Neoplasm Metastasis ,Cell Adhesion Molecules ,Neoplasm Transplantation ,Sequence Deletion - Abstract
Metastatic ovarian cancer has a dismal prognosis and current chemotherapeutic approaches have very limited success. Metadherin (MTDH) is expressed in human ovarian cancer tissue and its expression inversely correlates with patients overall survival. Consistent with these studies, we observed MTDH expression in tissue specimens of FIGO Stage III ovarian carcinomas (72/83 cases). However, we also observed this in normal human ovarian epithelial (OE) cells, which raised the question of whether MTDH-variants with functional differences exist. We identified a novel MTDH exon 11 skipping variant (MTDHdel) which was seen at higher levels in ovarian cancer compared to benign OE cells. We analyzed MTDH-binding partner interactions and found that 12 members of the small ribosomal subunit and several mRNA binding proteins bound stronger to MTDHdel than to wildtype MTDH which indicates differential effects on gene translation. Knockdown of MTDH in ovarian cancer cells reduced the amount of distant metastases and improved the survival of ovarian cancer-bearing mice. Selective overexpression of the MTDHdel enhanced murine and human ovarian cancer progression and caused a malignant phenotype in originally benign human OE cells. MTDHdel was detectable in microdissected ovarian cancer cells of some human tissue specimens of ovarian carcinomas. In summary, we have identified a novel MTDH exon 11 skipping variant that shows enhanced binding to small ribosomal subunit members and that caused reduced overall survival of ovarian cancer bearing mice. Based on the findings in the murine system and in human tissues, MTDHdel must be considered a major promalignant factor for ovarian cancer.
- Published
- 2014
13. Phase I trial of a novel intradermal idiotype vaccine in patients with advanced B-cell lymphoma: specific immune responses despite profound immunosuppression
- Author
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Katja Zirlik, Gabriele Ihorst, Cristina Bertinetti, Cornelius F. Waller, Kristina Heining-Mikesch, Heide Dierbach, and Hendrik Veelken
- Subjects
Idiotype ,Adult ,Male ,Cancer Research ,Lymphoma, B-Cell ,medicine.medical_treatment ,T-Lymphocytes ,Molecular Sequence Data ,Follicular lymphoma ,Epitopes, T-Lymphocyte ,Active immunotherapy ,Cancer Vaccines ,Immune system ,Immunoglobulin Idiotypes ,medicine ,Humans ,Amino Acid Sequence ,Aged ,B-Lymphocytes ,biology ,business.industry ,Vaccination ,Middle Aged ,medicine.disease ,Virology ,Treatment Outcome ,Oncology ,Immunization ,Immunology ,biology.protein ,Female ,Antibody ,business ,Adjuvant - Abstract
The immunoglobulin receptor of B-cell lymphomas constitutes a specific tumor antigen (idiotype) and a target for active immunotherapy. Encouraging results have been reported in phase II trials after s.c. vaccination of follicular lymphoma patients during clinical remission with idiotype produced from eukaryotic cell lines and coupled to an immunogenic carrier macromolecule. We have developed a good manufacturing protocol for rapid expression of idiotype vaccines as recombinant Fab fragments in Escherichia coli. The objectives of this trial were to show safety and feasibility of intradermal immunization with this vaccine and to investigate whether immune responses were induced by this immunization route. Patients (n = 18) with advanced B-cell malignancies received repetitive intradermal vaccinations with 0.5 to 1.65 mg recombinant idiotype Fab fragment mixed with lipid-based adjuvant in combination with 150 μg granulocyte macrophage colony-stimulating factor s.c. at the same location. The patients' immune status was assessed by flow cytometry of peripheral blood lymphocytes and concomitant hepatitis B vaccination. Cellular and humoral immune responses to the vaccine were assessed by enzyme-linked immunospot and ELISA. Side effects of a total of 65 vaccinations were mild and did not affect the immunization schedule. No patient developed hepatitis B surface antibodies (anti-HBs) after two hepatitis B immunizations. Of 17 evaluable patients, five developed specific anti-vaccine antibodies, and eight developed anti-Fab T-cell responses. T-cell reactivity was independent of the cellular immune status and was idiotype specific as shown by statistical regression analysis (P = 0.0024) and epitope mapping studies. Intradermal administration of uncoupled recombinant idiotype with appropriate adjuvants may overcome profound clinical immunosuppression and induce specific immune responses. (Cancer Res 2006; 66(8): 4496-502)
- Published
- 2006
14. Regulation of Immune Responses during Acute GvHD Via the IL-33/ST2 Axis
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Victor Tkachev, Elizabeth Lieberknecht, Jason Devlin, Tobias Junt, Marie Follo, Tobias Wertheimer, Heide Dierbach, Quan Liu, Gabriele Prinz, Annette Schmitt-Graeff, Simon C. Watkins, Brent H. Koehn, Bruce R. Blazar, Heth R. Turnquist, Natalie Stickel, Patricia A. Taylor, Susumu Nakae, Benjamin M. Matta, Dietmar Pfeifer, Max Warncke, Dawn K. Reichenbach, Justus Duyster, Vincent Schwarze, Robert Zeiser, James L.M. Ferrara, Lukas Schwab, and Yvonne Beck
- Subjects
Stromal cell ,Immunology ,Cell Biology ,Hematology ,Biology ,Biochemistry ,Interleukin 33 ,surgical procedures, operative ,Immune system ,Downregulation and upregulation ,Myeloid-derived Suppressor Cell ,Cytotoxic T cell ,Tumor necrosis factor alpha ,Interleukin 18 - Abstract
The IL-1 superfamily member IL-33 is produced in barrier tissues. IL-33 binds to the receptor suppression of tumorigenicity 2 (ST2), expressed on stromal cells, regulatory T cells (Tregs), myeloid derived suppressor cells (MDSCs), and macrophages. IL-33 has both anti-inflammatory and pro-inflammatory properties. It is not known if IL-33 plays a role in acute GvHD, and if so what properties it exerts. By immunohistochemistry staining of gut tissues, IL-33 production by non-hematopoietic cells was increased in mice post-conditioning and in patients during GvHD. To determine whether IL-33 could augment GvHD via a host signaling mechanism, we compared st2-/-to wildtype (wt) hosts and observed decreased GvHD lethality (Figure 1A). Additionally, IL-33-/- versus wt hosts had a marked decrease in GvHD lethality and reduced TNFα production. Conversely, IL-33 administration during the peak inflammatory response worsened GvHD. Previous studies have shown increased levels of the soluble form of ST2 (sST2) are a biomarker for steroid-refractory GvHD (Vander Lugt, NEJM, 2013). We hypothesized that sST2 acted not only as an indicator of tissue injury and biomarker of GvHD but also as an immune modulator during GvHD. In rodents, we found that ST2 was upregulated on alloreactive T cells and sST2 increased as GvHD progressed. St2-/-versus wt donor T cells had a marked reduction in GvHD lethality (Figure 1B) without compromise of graft-vs-leukemia responses. Comparable data was seen in 2 different strain combinations. Alloantigen-induced IL-18 receptor upregulation was significantly lower in the absence of ST2, which was linked to significantly reduced IFNγ production by st2-/- vs wt CD4 and CD8 T cells during GvHD. Similarly, sST2 transgenic hosts and wt recipients given exogenous sST2-Fc fusion protein infusions (Figure 1C) to block ST2/IL-33 interaction each had significantly reduced GVHD lethality, establishing the functional role of ST2 as a decoy receptor modulating GVHD. During the peak of the GvHD inflammatory response, IL-33 signalling of either donor or host cells promoted activation of donor T cells, while the use of exogenous sST2-Fc protein to prevent IL33/ST2 engagement ameliorates disease. Together, these studies point to targeting of the IL-33/ST2 axis as a novel and potent target for GvHD therapy. Disclosures Warncke: Novartis Pharma AG: Employment. Junt:Novartis Pharma AG: Employment.
- Published
- 2014
15. Murine dendritic cells generated under serum-free conditions have a mature phenotype and efficiently induce primary immune responses
- Author
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Heide Dierbach, Hendrik Veelken, Marie Follo, Max Warncke, and Anna Dodero
- Subjects
medicine.medical_treatment ,T cell ,Immunology ,Cell Culture Techniques ,Biology ,Immunotherapy, Adoptive ,Culture Media, Serum-Free ,Immunophenotyping ,Interferon-gamma ,Mice ,Immune system ,Antigen ,Antigens, CD ,Antigens, Neoplasm ,medicine ,Immunology and Allergy ,Animals ,CD86 ,MHC class II ,Mice, Inbred BALB C ,Microscopy, Confocal ,Cell Differentiation ,Immunotherapy ,Dendritic cell ,Dendritic Cells ,Flow Cytometry ,Interleukin-12 ,Peptide Fragments ,Specific Pathogen-Free Organisms ,medicine.anatomical_structure ,Cancer research ,biology.protein ,CD80 - Abstract
Vaccination with in vitro-generated dendritic cells (DC) that present tumor-associated antigens is a promising approach for immunotherapy of malignant tumors. For optimization of DC-based vaccination protocols, preclinical tumor models that mimic the clinical situation closely are highly desirable. Strong non-specific T cell activation was observed in experimental immunization of mice with syngeneic DC generated in standard FCS-supplemented culture medium. To avoid deviation of the immune response to FCS-derived antigens, a serum-free culture protocol for in vitro generation of murine DC from bone marrow progenitor cells was developed. In comparison to DC differentiated with FCS supplementation, DC generated under serum-free conditions (sfDC) have a more homogeneous phenotype with higher expression of IL-12 and the differentiation and activation markers CD11c, CD40, CD80, CD83, CD86, DEC-205, and MHC class II. Demonstration of strong uptake of protein and carbohydrate antigens and analysis of the in vivo migration behaviour of sfDC also indicated excellent APC function. Vaccination of mice with peptide-pulsed sfDC efficiently induced an antigen-specific T cell response as assessed by MHC tetramer staining, IFN-gamma ELISPOT and in vivo cytotoxicity assay. sfDC may therefore represent a valuable tool to improve active tumor immunotherapy in animal models.
- Published
- 2005
16. MiR-155 Regulates Acute GvHD By Reducing NLRP3 Inflammasome Activity Via Targeting SOCS1 In Antigen-Presenting Cells
- Author
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Sophia Chen, Joseena Iype, Sebastian Grundmann, Marco Idzko, Annette Schmitt-Gräff, Heide Dierbach, Yvonne Beck, Jürgen Finke, Justus Duyster, and Robert Zeiser
- Subjects
Adoptive cell transfer ,business.industry ,medicine.medical_treatment ,Immunology ,Caspase 1 ,Inflammasome ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Proinflammatory cytokine ,Cytokine ,Immune system ,Graft-versus-host disease ,medicine ,Antigen-presenting cell ,business ,medicine.drug - Abstract
Allogeneic hematopoietic cell transplantation (alloHCT) is limited by acute graft-versus-host disease (GvHD) which occurs in 30-40 % of patients. Despite numerous clinical studies, the standard immunosuppressive regimens for prevention of acute GvHD have changed little in the last two decades. A better understanding of the pathophysiology of GvHD may help to improve the outcome after alloHCT. Acute GvHD is mediated by donor T cells that are activated by recipient antigen-presenting cells (APCs). Since microRNA-155 (miR-155) was shown to regulate the activation of different innate immune cell subsets, we aimed to determine its function for APCs during an allogeneic immune response. We observed upregulation of miR-155 in recipient APCs residing in secondary lymphoid organs and in the intestinal tract when GvHD developed. By using gene targeted mice, we observed that miR-155 deficiency of the recipient led to improved survival (p=0.0011), lower GvHD histopathology scores (small bowel: p=0.0003, large bowel: p=0.0209, liver: p=0.0035) and reduced serum levels of proinflammatory cytokines (IFNγ: p=0.0305, IL-12: p=0.0274, MCP-1: p=0.0016). Using miR-155-/- bone marrow chimeric mice lacking miR-155 in the hematopoietic system and adoptive transfer of miR-155+/+ versus miR-155-/- APCs, we determined that this phenotype was dependent on miR-155 deficiency in the APC compartment. Mechanistically, miR-155-/- APCs showed reduced ERK phosphorylation in response to lipopolysaccharides (LPS) and adenosine-5'-triphosphate (ATP) as compared to miR-155+/+ APCs. Cleaved caspase-1, the indicator of an active NLRP3 inflammasome, was also reduced in miR-155-/- APCs. Conversely, suppressor of cytokine signaling 1 (SOCS1), a known target of miR-155, was increased in miR-155-/- APCs as compared to miR-155+/+ APCs. SOCS1 leads to proteasomal degradation of the p65 subunit of NF-κB and thereby may interfere with NLRP3 inflammasome activation. Overall, our data indicate that miR-155 is required in the recipient APC compartment for NLRP3 inflammasome activation in response to LPS and ATP. These findings could help to reduce tissue damage related proinflammatory effects induced by LPS and ATP which activate the intestinal immune system following cytotoxic therapy by antagonizing miR-155 function with antagomir treatment. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2013
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