Heide Dierbach
University Medical Center Freiburg
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Publication
Featured researches published by Heide Dierbach.
Blood | 2015
Dawn K. Reichenbach; Vincent Schwarze; Benjamin M. Matta; Victor Tkachev; Elisabeth Lieberknecht; Quan Liu; Brent H. Koehn; Dietmar Pfeifer; Patricia A. Taylor; Gabriele Prinz; Heide Dierbach; Natalie Stickel; Yvonne Beck; Max Warncke; Tobias Junt; Annette Schmitt-Graeff; Susumu Nakae; Marie Follo; Tobias Wertheimer; Lukas Schwab; Jason Devlin; Simon C. Watkins; Justus Duyster; James L.M. Ferrara; Heth R. Turnquist; Robert Zeiser; Bruce R. Blazar
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.
Blood | 2013
Franziska Leonhardt; Sebastian Grundmann; Martin Behe; Franziska Bluhm; Rebecca A. Dumont; Friederike Braun; Melpomeni Fani; Katarina Riesner; Gabriele Prinz; Anne-Kathrin Hechinger; Ulrike V. Gerlach; Heide Dierbach; Olaf Penack; Annette Schmitt-Gräff; Jürgen Finke; Wolfgang A. Weber; Robert Zeiser
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.
Blood | 2015
Anne Kathrin Hechinger; Benjamin A.H. Smith; Ryan Flynn; Kathrin Hanke; Cameron McDonald-Hyman; Patricia A. Taylor; Dietmar Pfeifer; Björn Hackanson; Franziska Leonhardt; Gabriele Prinz; Heide Dierbach; Annette Schmitt-Graeff; Jiri Kovarik; Bruce R. Blazar; Robert Zeiser
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.
Journal of Immunology | 2015
Verena Klämbt; Sebastian A. Wohlfeil; Lukas Schwab; Jan Hülsdünker; Korcan Ayata; Petya Apostolova; Annette Schmitt-Graeff; Heide Dierbach; Gabriele Prinz; Marie Follo; Marco Prinz; Marco Idzko; Robert Zeiser
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.
International Journal of Cancer | 2015
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; Robert Zeiser
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.
Blood | 2018
Jan Hülsdünker; Katja J. Ottmüller; Hannes Philipp Neeff; Motoko Koyama; Zhan Gao; Oliver S. Thomas; Marie Follo; Ali Al-Ahmad; Gabriele Prinz; Sandra Duquesne; Heide Dierbach; Susanne Kirschnek; Tim Lämmermann; Martin J. Blaser; Brian T. Fife; Bruce R. Blazar; Andreas Beilhack; Geoffrey R. Hill; Georg Häcker; Robert Zeiser
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.
Oncotarget | 2017
Hana Andrlová; Justin Mastroianni; Josef Madl; Johannes S. Kern; Wolfgang Melchinger; Heide Dierbach; Florian Wernet; Marie Follo; Kristin Technau-Hafsi; Cristina Has; Venugopal Rao Mittapalli; Marco Idzko; Ricarda Herr; Tilman Brummer; Hendrik Ungefroren; Hauke Busch; Melanie Boerries; Andreas Narr; Gabriele Ihorst; Claire Vennin; Annette Schmitt-Graeff; Susana Minguet; Paul Timpson; Justus Duyster; Frank Meiss; Winfried Römer; Robert Zeiser
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.
Cancer Research | 2006
Cristina Bertinetti; Katja Zirlik; Kristina Heining-Mikesch; Gabriele Ihorst; Heide Dierbach; Cornelius F. Waller; Hendrik Veelken
Journal of Immunological Methods | 2006
Max Warncke; Anna Dodero; Heide Dierbach; Marie Follo; Hendrik Veelken
Biology of Blood and Marrow Transplantation | 2016
Jan Hülsdünker; Gabriele Prinz; Katja J. Ottmüller; Heide Dierbach; Marie Follo; Susanne Kirschnek; Andreas Beilhack; Georg Häcker; Robert Zeiser