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Institute
- Medizinische Klinik und Poliklinik II (570)
- Theodor-Boveri-Institut für Biowissenschaften (34)
- Pathologisches Institut (30)
- Klinik und Poliklinik für Nuklearmedizin (25)
- Graduate School of Life Sciences (24)
- Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I) (23)
- Medizinische Klinik und Poliklinik I (19)
- Institut für Virologie und Immunbiologie (18)
- Kinderklinik und Poliklinik (16)
- Comprehensive Cancer Center Mainfranken (14)
Schriftenreihe
Sonstige beteiligte Institutionen
- Johns Hopkins School of Medicine (3)
- Center for Interdisciplinary Clinical Research, Würzburg University, Würzburg, Germany (2)
- Betriebsärztlicher Dienst der Universität Würzburg (1)
- Clinical Trial Center (CTC) / Zentrale für Klinische Studien Würzburg (ZKSW) (1)
- Department of Hematology and Oncology, Sana Hospital Hof, Hof, Germany (1)
- Department of Laboratory Medicine and Medicine Huddinge, Karolinska Institutet and University Hospital, Stockholm, Sweden (1)
- Department of Medicine A, University Hospital of Münster, Münster, Germany (1)
- Early Clinical Trial Unit, Comprehensive Cancer Center Mainfranken (1)
- Experimentelle Tumorimmunologie, Frauenklinik, Universität Würzburg (1)
- Interdisciplinary Center for Clinical Research (IZKF), Würzburg, Germany (1)
ResearcherID
- N-2030-2015 (1)
Weiss, Esther ; Ziegler, Sabrina ; Fliesser, Mirjam ; Schmitt, Anna-Lena ; Hünniger, Kerstin ; Kurzai, Oliver ; Morton, Charles-Oliver ; Einsele, Hermann ; Loeffler, Juergen
Invasive aspergillosis (IA) is an infectious disease caused by the fungal pathogen Aspergillus fumigatus that mainly affects immunocompromised hosts. To investigate immune cell cross-talk during infection with A. fumigatus, we co-cultured natural killer (NK) cells and dendritic cells (DC) after stimulation with whole fungal structures, components of the fungal cell wall, fungal lysate or ligands for distinct fungal receptors. Both cell types showed activation after stimulation with fungal components and were able to transfer activation signals to the counterpart not stimulated cell type. Interestingly, DCs recognized a broader spectrum of fungal components and thereby initiated NK cell activation when those did not recognize fungal structures. These experiments highlighted the supportive function of DCs in NK cell activation. Furthermore, we focused on soluble DC mediated NK cell activation and showed that DCs stimulated with the TLR2/Dectin-1 ligand zymosan could maximally stimulate the expression of CD69 on NK cells. Thus, we investigated the influence of both receptors for zymosan, Dectin-1 and TLR2, which are highly expressed on DCs but show only minimal expression on NK cells. Specific focus was laid on the question whether Dectin-1 or TLR2 signaling in DCs is important for the secretion of soluble factors leading to NK cell activation. Our results show that Dectin-1 and TLR2 are negligible for NK cell activation. We conclude that besides Dectin-1 and TLR2 other receptors on DCs are able to compensate for the missing signal.
B cell-derived interleukin-10 (IL-10) production has been described as a hallmark for regulatory function in B lymphocytes. However, there is an ongoing debate on the origin of IL-10-secreting B cells and lack of specific surface markers has turned into an important obstacle for studying human B regulatory cells. In this study, we propose that tumor necrosis factor receptor 2 (TNFR2) expression can be used for enrichment of IL-10-secreting B cells. Our data confirm that IL-10 production can be induced by TLR9 stimulation with CpG ODN and that IL-10 secretion accompanies differentiation of peripheral blood B cells into plasma blasts. We further show that CpG ODN stimulation induces TNFR2 expression, which correlates with IL-10 secretion and terminal differentiation. Indeed, flow cytometric sorting of TNFR2+ B cells revealed that TNFR2+ and TNFR2− fractions correspond to IL-10+ and IL-10− fractions, respectively. Furthermore, CpG-induced TNFR2+ B cells were predominantly found in the IgM+ CD27+ B cell subset and spontaneously released immunoglobulin. Finally, our data corroborate the functional impact of TNFR2 by demonstrating that stimulation with a TNFR2 agonist significantly augments IL-10 and IL-6 production in B cells. Altogether, our data highlight a new role for TNFR2 in IL-10-secreting human B lymphocytes along with the potential to exploit this finding for sorting and isolation of this currently ill-defined B cell subset.
Progranulin (PGRN) is a secreted anti-inflammatory protein which can be processed by neutrophil proteases to various granulins. It has been reported that at least a significant portion of the anti-inflammatory effects of PGRN is due to direct high affinity binding to tumor necrosis factor receptor-1 (TNFR1) and TNFR2 and inhibition of tumor necrosis factor (TNF)-induced TNFR1/2 signaling. Two studies failed to reproduce the interaction of TNFR1 and TNFR2 with PGRN, but follow up reports speculated that this was due to varying experimental circumstances and/or the use of PGRN from different sources. However, even under consideration of these speculations, there is still a striking discrepancy in the literature between the concentrations of PGRN needed to inhibit TNF signaling and the concentrations required to block TNF binding to TNFR1 and TNFR2. While signaling events induced by 0.2–2 nM of TNF have been efficiently inhibited by low, near to equimolar concentrations (0.5–2.5 nM) of PGRN in various studies, the reported inhibitory effects of PGRN on TNF-binding to TNFR1/2 required a huge excess of PGRN (100–1,000-fold). Therefore, we investigated the effect of PGRN on TNF binding to TNFR1 and TNFR2 in highly sensitive cellular binding studies. Unlabeled TNF inhibited >95% of the specific binding of a Gaussia princeps luciferase (GpL) fusion protein of TNF to TNFR1 and TNFR2 and blocked binding of soluble GpL fusion proteins of TNFR1 and TNFR2 to membrane TNF expressing cells to >95%, too. Purified PGRN, however, showed in both assays no effect on TNF–TNFR1/2 interaction even when applied in huge excess. To rule out that tags and purification- or storage-related effects compromise the potential ability of PGRN to bind TNF receptors, we directly co-expressed PGRN, and as control TNF, in TNFR1- and TNFR2-expressing cells and looked for binding of GpL-TNF. While expression of TNF strongly inhibited binding of GpL-TNF to TNFR1/2, co-expression of PGRN had not effect on the ability of the TNFR1/2-expressing cells to bind TNF.
Jarick, Katja J. ; Mokhtari, Zeinab ; Scheller, Lukas ; Hartweg, Julia ; Thusek, Sina ; Le, Duc-Dung ; Ranecky, Maria ; Shaikh, Haroon ; Qureischi, Musga ; Heinze, Katrin G. ; Beilhack, Andreas
The regulation of immune cell migration throughout the body is essential to warrant immunosurveillance and to maintain immune homeostasis. Marking and tracking of these cells has proven important to study mechanisms of immune cell trafficking and cell interaction in vivo. Photoconversion is a well-suited technique for intravital application because it enables contactless time- and location-specific marking of cells in the tissue without surgically manipulating the microenvironment of the cells in question. However, in dividing cells the converted fluorescent protein may decline quickly. Here, we provide a detailed description of the photoconversion technique and its applicability to tracking highly proliferating T cells from the priming site of T cell activation to peripheral target organs of effector function in a preclinical model. Dendra2+ T cells were photoconverted in the Peyer’s patches during the initiation phase of acute graft-versus-host disease (GvHD) and tracked through the mesenteric lymph nodes and the peripheral blood to the small intestine with flow cytometry and intravital two-photon microscopy. Photoconverted alloreactive T cells preserved the full proliferative capacity, homing, and migration of alloreactive T cells in the intestinal lamina propria. We conclusively proved that photoconversion of highly proliferative alloreactive T cells in the Peyer’s patches is an effective tool to study trafficking of alloreactive T cells under physiologic conditions and to GvHD target tissues. This technique can also be applied to the study of immune cell tracking under inflammatory and non-inflammatory conditions.
OSM, ein Vertreter der IL-6-Typ-Zytokine, ist nicht nur für entzündliche, sondern auch für metabolische Prozesse von Bedeutung. Vorarbeiten der Arbeitsgruppe GEIER/HERMANNS und Studien von KOMORI et al. legen protektive Eigenschaften des Zytokins nahe, da Mäuse, denen OSMR fehlte, Charakteristika des metabolischen Syndroms aufwiesen. Zur eingehenderen Untersuchung der von OSM vermittelten Wirkung auf den murinen Lipidstoffwechsel wurden zwei für die NAFLD und Atherosklerose anfällige Modelle herangezogen und jeweils in Gegenwart und Abwesenheit des Osmr studiert: Weibliche Apoe-/-(Osmr-/-) und Ldlr-/-(Osmr-/-) Mäuse wurden über einen Zeitraum von zwölf Wochen mit westlicher Diät gefüttert, wöchentlich gewogen, am Ende der Diät geopfert und geerntet. Wildtypische C57Bl/6-Mäuse erfuhren die gleiche Behandlung und dienten als Referenzgruppe. Im Rahmen des Promotionsprojektes wurden Leberfettgehalt, Serumlipidspiegel, Lipoproteinfraktionen und Stuhllipide von Apoe-deletierten Mäusen bestimmt und mit bereits vorhandenen Daten der Ldlr-/-(Osmr-/-) und wildtypischen Mäuse in Beziehung gesetzt. Expressionsanalysen von am Lipidstoffwechsel beteiligten Genen in Darm-, Leber- und Fettgewebe trugen dazu bei, OSM-abhängige Regulationen aufzudecken.
Ldlr-/- Tiere nahmen unter der Diät exzessiv zu, hatten hohe Serumspiegel an Leptin, Gluco-se und Lipiden, eine Lebersteatose und, begleitet von einer Induktion des Vldlr, erhöhte inflammatorische Marker im visceralen Fettgewebe. Der zusätzliche Knockout des Osmr ging mit einer geringeren Vldlr-Expression im Fettgewebe und einer hepatozytären Induktion von Cyp7a1 einher und resultierte in einem metabolisch günstigeren Phänotyp. Apoe-defiziente Tiere unterschieden sich hinsichtlich ihrer Gewichtszunahme nicht von Ldlr-/-Osmr-/- und C57Bl/6-Mäusen. Überraschenderweise zeigten sich im Serum von Apoe-/-Osmr-/- jedoch gegenüber Apoe-/- Mäusen erhöhte Konzentrationen des Gesamt- und VLDL-Cholesterins, der Triglyceride und freien Fettsäuren. Obwohl Lebern der Apoe-/-Osmr-/- Mäuse geringere Ldlr- und Lrp1-mRNA-Spiegel als die der Apoe-/- Mäuse aufwiesen, hatten sie einen höheren hepatischen Cholesteringehalt. Bei gesteigerter Cpt1a-Expression fiel der hepatische Tri-glyceridgehalt Apoe-deletierter Mäuse geringer aus als in Ldlr-/-(Osmr-/-) und wildtypischen Tieren. Unter Umgehung einer Fettgewebsentzündung präsentierten Apoe-defiziente Mäuse Hinweise einer inflammatorischen Leberschädigung, die pathogenetisch am ehesten mit einer gestörten Cholesterinhomöostase in Verbindung zu bringen war.
Abhängig vom genetischen Hintergrund des Mausmodells hatte OSM schützende oder schädliche Effekte auf den Lipidmetabolismus. Die Ergebnisse der vorliegenden Arbeit betonen die entscheidende Bedeutung entzündlicher, von OSM modulierter Prozesse für den Fettstoffwechsel in Leber- und Fettgewebe. Weiterführende Experimente sind nötig, um die den Beobachtungen zugrunde liegenden molekularen Mechanismen zu entschlüsseln.
Ludwig, Heinz ; Delforge, Michel ; Facon, Thierry ; Einsele, Hermann ; Gay, Francesca ; Moreau, Philippe ; Avet-Loiseau, Hervé ; Boccadoro, Mario ; Hajek, Roman ; Mohty, Mohamad ; Cavo, Michele ; Dimopoulos, Meletios A ; San-Miguel, Jesús F ; Terpos, Evangelos ; Zweegman, Sonja ; Garderet, Laurent ; Mateos, María-Victoria ; Cook, Gordon ; Leleu, Xavier ; Goldschmidt, Hartmut ; Jackson, Graham ; Kaiser, Martin ; Weisel, Katja ; van de Donk, Niels W. C. J. ; Waage, Anders ; Beksac, Meral ; Mellqvist, Ulf H. ; Engelhardt, Monika ; Caers, Jo ; Driessen, Christoph ; Bladé, Joan ; Sonneveld, Pieter
During the last few years, several new drugs have been introduced for treatment of patients with multiple myeloma, which have significantly improved the treatment outcome. All of these novel substances differ at least in part in their mode of action from similar drugs of the same drug class, or are representatives of new drug classes, and as such present with very specific side effect profiles. In this review, we summarize these adverse events, provide information on their prevention, and give practical guidance for monitoring of patients and for management of adverse events.
Went, Molly ; Sud, Amit ; Speedy, Helen ; Sunter, Nicola J. ; Försti, Asta ; Law, Philip J. ; Johnson, David C. ; Mirabella, Fabio ; Holroyd, Amy ; Li, Ni ; Orlando, Giulia ; Weinhold, Niels ; van Duin, Mark ; Chen, Bowang ; Mitchell, Jonathan S. ; Mansouri, Larry ; Juliusson, Gunnar ; Smedby, Karin E ; Jayne, Sandrine ; Majid, Aneela ; Dearden, Claire ; Allsup, David J. ; Bailey, James R. ; Pratt, Guy ; Pepper, Chris ; Fegan, Chris ; Rosenquist, Richard ; Kuiper, Rowan ; Stephens, Owen W. ; Bertsch, Uta ; Broderick, Peter ; Einsele, Hermann ; Gregory, Walter M. ; Hillengass, Jens ; Hoffmann, Per ; Jackson, Graham H. ; Jöckel, Karl-Heinz ; Nickel, Jolanta ; Nöthen, Markus M. ; da Silva Filho, Miguel Inacio ; Thomsen, Hauke ; Walker, Brian A. ; Broyl, Annemiek ; Davies, Faith E. ; Hansson, Markus ; Goldschmidt, Hartmut ; Dyer, Martin J. S. ; Kaiser, Martin ; Sonneveld, Pieter ; Morgan, Gareth J. ; Hemminki, Kari ; Nilsson, Björn ; Catovsky, Daniel ; Allan, James M. ; Houlston, Richard S.
The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (Rg = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies.
Walker, Brian A. ; Mavrommatis, Konstantinos ; Wardell, Christopher P. ; Ashby, T. Cody ; Bauer, Michael ; Davies, Faith ; Rosenthal, Adam ; Wang, Hongwei ; Qu, Pingping ; Hoering, Antje ; Samur, Mehmet ; Towfic, Fadi ; Ortiz, Maria ; Flynt, Erin ; Yu, Zhinuan ; Yang, Zhihong ; Rozelle, Dan ; Obenauer, John ; Trotter, Matthew ; Auclair, Daniel ; Keats, Jonathan ; Bolli, Niccolo ; Fulciniti, Mariateresa ; Szalat, Raphael ; Moreau, Phillipe ; Durie, Brian ; Stewart, A. Keith ; Goldschmidt, Hartmut ; Raab, Marc S. ; Einsele, Hermann ; Sonneveld, Pieter ; San Miguel, Jesus ; Lonial, Sagar ; Jackson, Graham H. ; Anderson, Kenneth C. ; Avet-Loiseau, Herve ; Munshi, Nikhil ; Thakurta, Anjan ; Morgan, Gareth
Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior. Whole-genome and exome data from 1273 NDMM patients identified genetic factors that contribute significantly to progression free survival (PFS) and overall survival (OS) (cumulative R2 = 18.4% and 25.2%, respectively). Integrating DNA drivers and clinical data into a Cox model using 784 patients with ISS, age, PFS, OS, and genomic data, the model has a cumlative R2 of 34.3% for PFS and 46.5% for OS. A high-risk subgroup was defined by recursive partitioning using either a) bi-allelic TP53 inactivation or b) amplification (≥4 copies) of CKS1B (1q21) on the background of International Staging System III, comprising 6.1% of the population (median PFS = 15.4 months; OS = 20.7 months) that was validated in an independent dataset. Double-Hit patients have a dire prognosis despite modern therapies and should be considered for novel therapeutic approaches.
Solimando, A G ; Brandl, A ; Mattenheimer, K ; Graf, C ; Ritz, M ; Ruckdeschel, A ; Stühmer, T ; Mokhtari, Z ; Rudelius, M ; Dotterweich, J ; Bittrich, M ; Desantis, V ; Ebert, R ; Trerotoli, P ; Frassanito, M A ; Rosenwald, A ; Vacca, A ; Einsele, H ; Jakob, F ; Beilhack, A
Cell adhesion in the multiple myeloma (MM) microenvironment has been recognized as a major mechanism of MM cell survival and the development of drug resistance. Here we addressed the hypothesis that the protein junctional adhesion molecule-A (JAM-A) may represent a novel target and a clinical biomarker in MM. We evaluated JAM-A expression in MM cell lines and in 147 MM patient bone marrow aspirates and biopsies at different disease stages. Elevated JAM-A levels in patient-derived plasma cells were correlated with poor prognosis. Moreover, circulating soluble JAM-A (sJAM-A) levels were significantly increased in MM patients as compared with controls. Notably, in vitro JAM-A inhibition impaired MM migration, colony formation, chemotaxis, proliferation and viability. In vivo treatment with an anti-JAM-A monoclonal antibody (αJAM-A moAb) impaired tumor progression in a murine xenograft MM model. These results demonstrate that therapeutic targeting of JAM-A has the potential to prevent MM progression, and lead us to propose JAM-A as a biomarker in MM, and sJAM-A as a serum-based marker for clinical stratification.
Sirtl, Simon ; Knoll, Gertrud ; Dieu Thuy, Trinh ; Lang, Isabell ; Siegmund, Daniela ; Gross, Stefanie ; Schuler-Thurner, Beatrice ; Neubert, Patrick ; Jantsch, Jonathan ; Wajant, Harald ; Ehrenschwender, Martin
Attempts to exploit the cytotoxic activity of death receptors (DR) for treating cancer have thus far been disappointing. DR activation in most malignant cells fails to trigger cell death and may even promote tumor growth by activating cell death-independent DR-associated signaling pathways. Overcoming apoptosis resistance is consequently a prerequisite for successful clinical exploitation of DR stimulation. Here we show that hyperosmotic stress in the tumor microenvironment unleashes the deadly potential of DRs by enforcing BCL-2 addiction of cancer cells. Hypertonicity robustly enhanced cytotoxicity of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and other DR ligands in various cancer entities. Initial events in TRAIL DR signaling remained unaffected, but hypertonic conditions unlocked activation of the mitochondrial death pathway and thus amplified the apoptotic signal. Mechanistically, we demonstrate that hyperosmotic stress imposed a BCL-2-addiction on cancer cells to safeguard the integrity of the outer mitochondrial membrane (OMM), essentially exhausting the protective capacity of BCL-2-like pro-survival proteins. Deprivation of these mitochondrial safeguards licensed DR-generated truncated BH3-interacting domain death agonist (tBID) to activate BCL-2-associated X protein (BAX) and initiated mitochondrial outer membrane permeabilization (MOMP). Our work highlights that hyperosmotic stress in the tumor environment primes mitochondria for death and lowers the threshold for DR-induced apoptosis. Beyond TRAIL-based therapies, our findings could help to strengthen the efficacy of other apoptosis-inducing cancer treatment regimens.