@article{DotterweichTowerBrandletal.2016,
  author    = {Dotterweich, Julia and Tower, Robert J. and Brandl, Andreas and M{\"u}ller, Marc and Hofbauer, Lorenz C. and Beilhack, Andreas and Ebert, Regina and Gl{\"u}er, Claus C. and Tiwari, Sanjay and Sch{\"u}tze, Norbert and Jakob, Franz},
  title     = {The KISS1 Receptor as an In Vivo Microenvironment Imaging Biomarker of Multiple Myeloma Bone Disease},
  series = {PLoS One},
  volume    = {11},
  journal   = {PLoS One},
  number    = {5},
  doi       = {10.1371/journal.pone.0155087},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146960},
  pages     = {e0155087},
  year      = {2016},
  abstract  = {Multiple myeloma is one of the most common hematological diseases and is characterized by an aberrant proliferation of plasma cells within the bone marrow. As a result of crosstalk between cancer cells and the bone microenvironment, bone homeostasis is disrupted leading to osteolytic lesions and poor prognosis. Current diagnostic strategies for myeloma typically rely on detection of excess monoclonal immunoglobulins or light chains in the urine or serum. However, these strategies fail to localize the sites of malignancies. In this study we sought to identify novel biomarkers of myeloma bone disease which could target the malignant cells and/or the surrounding cells of the tumor microenvironment. From these studies, the KISS1 receptor (KISS1R), a G-protein-coupled receptor known to play a role in the regulation of endocrine functions, was identified as a target gene that was upregulated on mesenchymal stem cells (MSCs) and osteoprogenitor cells (OPCs) when co-cultured with myeloma cells. To determine the potential of this receptor as a biomarker, in vitro and in vivo studies were performed with the KISS1R ligand, kisspeptin, conjugated with a fluorescent dye. In vitro microscopy showed binding of fluorescently-labeled kisspeptin to both myeloma cells as well as MSCs under direct co-culture conditions. Next, conjugated kisspeptin was injected into immune-competent mice containing myeloma bone lesions. Tumor-burdened limbs showed increased peak fluorescence compared to contralateral controls. These data suggest the utility of the KISS1R as a novel biomarker for multiple myeloma, capable of targeting both tumor cells and host cells of the tumor microenvironment.},
  language  = {en}
}
@article{DietlSchwinnDietletal.2016,
  author    = {Dietl, Sebastian and Schwinn, Stefanie and Dietl, Susanne and Riedl, Simone and Deinlein, Frank and Rutkowski, Stefan and von Bueren, Andre O. and Krauss, J{\"u}rgen and Schweitzer, Tilmann and Vince, Giles H. and Picard, Daniel and Eyrich, Matthias and Rosenwald, Andreas and Ramaswamy, Vijay and Taylor, Michael D. and Remke, Marc and Monoranu, Camelia M. and Beilhack, Andreas and Schlegel, Paul G. and W{\"o}lfl, Matthias},
  title     = {MB3W1 is an orthotopic xenograft model for anaplastic medulloblastoma displaying cancer stem cell- and Group 3-properties},
  series = {BMC Cancer},
  volume    = {16},
  journal   = {BMC Cancer},
  number    = {115},
  doi       = {10.1186/s12885-016-2170-z},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-145877},
  year      = {2016},
  abstract  = {Background Medulloblastoma is the most common malignant brain tumor in children and can be divided in different molecular subgroups. Patients whose tumor is classified as a Group 3 tumor have a dismal prognosis. However only very few tumor models are available for this subgroup. Methods We established a robust orthotopic xenograft model with a cell line derived from the malignant pleural effusions of a child suffering from a Group 3 medulloblastoma. Results Besides classical characteristics of this tumor subgroup, the cells display cancer stem cell characteristics including neurosphere formation, multilineage differentiation, CD133/CD15 expression, high ALDH-activity and high tumorigenicity in immunocompromised mice with xenografts exactly recapitulating the original tumor architecture. Conclusions This model using unmanipulated, human medulloblastoma cells will enable translational research, specifically focused on Group 3 medulloblastoma.},
  language  = {en}
}
@article{ChopraBiehlSteinfattetal.2016,
  author    = {Chopra, Martin and Biehl, Marlene and Steinfatt, Tim and Brandl, Andreas and Kums, Juliane and Amich, Jorge and Vaeth, Martin and Kuen, Janina and Holtappels, Rafaela and Podlech, J{\"u}rgen and Mottok, Anja and Kraus, Sabrina and Jord{\´a}n-Garotte, Ana-Laura and B{\"a}uerlein, Carina A. and Brede, Christian and Ribechini, Eliana and Fick, Andrea and Seher, Axel and Polz, Johannes and Ottmueller, Katja J. and Baker, Jeannette and Nishikii, Hidekazu and Ritz, Miriam and Mattenheimer, Katharina and Schwinn, Stefanie and Winter, Thorsten and Sch{\"a}fer, Viktoria and Krappmann, Sven and Einsele, Hermann and M{\"u}ller, Thomas D. and Reddehase, Matthias J. and Lutz, Manfred B. and M{\"a}nnel, Daniela N. and Berberich-Siebelt, Friederike and Wajant, Harald and Beilhack, Andreas},
  title     = {Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion},
  series = {Journal of Experimental Medicine},
  volume    = {213},
  journal   = {Journal of Experimental Medicine},
  number    = {9},
  doi       = {10.1084/jem.20151563},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-187640},
  pages     = {1881-1900},
  year      = {2016},
  abstract  = {Donor CD4\(^+\)Foxp3\(^+\) regulatory T cells (T reg cells) suppress graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HCT allo-HCT]). Current clinical study protocols rely on the ex vivo expansion of donor T reg cells and their infusion in high numbers. In this study, we present a novel strategy for inhibiting GvHD that is based on the in vivo expansion of recipient T reg cells before allo-HCT, exploiting the crucial role of tumor necrosis factor receptor 2 (TNFR2) in T reg cell biology. Expanding radiation-resistant host T reg cells in recipient mice using a mouse TNFR2-selective agonist before allo-HCT significantly prolonged survival and reduced GvHD severity in a TNFR2-and T reg cell-dependent manner. The beneficial effects of transplanted T cells against leukemia cells and infectious pathogens remained unaffected. A corresponding human TNFR2-specific agonist expanded human T reg cells in vitro. These observations indicate the potential of our strategy to protect allo-HCT patients from acute GvHD by expanding T reg cells via selective TNFR2 activation in vivo.},
  language  = {en}
}
@article{BeilhackChopraKrausetal.2013,
  author    = {Beilhack, Andreas and Chopra, Martin and Kraus, Sabrina and Schwinn, Stefanie and Ritz, Miriam and Mattenheimer, Katharina and Mottok, Anja and Rosenwald, Andreas and Einsele, Hermann},
  title     = {Non-Invasive Bioluminescence Imaging to Monitor the Immunological Control of a Plasmablastic Lymphoma-Like B Cell Neoplasia after Hematopoietic Cell Transplantation},
  doi       = {10.1371/journal.pone.0081320},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-111341},
  year      = {2013},
  abstract  = {To promote cancer research and to develop innovative therapies, refined pre-clinical mouse tumor models that mimic the actual disease in humans are of dire need. A number of neoplasms along the B cell lineage are commonly initiated by a translocation recombining c-myc with the immunoglobulin heavy-chain gene locus. The translocation is modeled in the C.129S1-Ighatm1(Myc)Janz/J mouse which has been previously engineered to express c-myc under the control of the endogenous IgH promoter. This transgenic mouse exhibits B cell hyperplasia and develops diverse B cell tumors. We have isolated tumor cells from the spleen of a C.129S1-Ighatm1(Myc)Janz/J mouse that spontaneously developed a plasmablastic lymphoma-like disease. These cells were cultured, transduced to express eGFP and firefly luciferase, and gave rise to a highly aggressive, transplantable B cell lymphoma cell line, termed IM380. This model bears several advantages over other models as it is genetically induced and mimics the translocation that is detectable in a number of human B cell lymphomas. The growth of the tumor cells, their dissemination, and response to treatment within immunocompetent hosts can be imaged non-invasively in vivo due to their expression of firefly luciferase. IM380 cells are radioresistant in vivo and mice with established tumors can be allogeneically transplanted to analyze graft-versus-tumor effects of transplanted T cells. Allogeneic hematopoietic stem cell transplantation of tumor-bearing mice results in prolonged survival. These traits make the IM380 model very valuable for the study of B cell lymphoma pathophysiology and for the development of innovative cancer therapies.},
  language  = {en}
}
@article{RiedelMottokBredeetal.2012,
  author    = {Riedel, Simone S. and Mottok, Anja and Brede, Christian and B{\"a}uerlein, Carina A. and Jord{\´a}n Garrote, Ana Laura and Ritz, Miriam and Mattenheimer, Katharina and Rosenwald, Andreas and Einsele, Hermann and Bogen, Bjarne and Beilhack, Andreas},
  title     = {Non-Invasive Imaging Provides Spatiotemporal Information on Disease Progression and Response to Therapy in a Murine Model of Multiple Myeloma},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-77978},
  year      = {2012},
  abstract  = {Background: Multiple myeloma (MM) is a B-cell malignancy, where malignant plasma cells clonally expand in the bone marrow of older people, causing significant morbidity and mortality. Typical clinical symptoms include increased serum calcium levels, renal insufficiency, anemia, and bone lesions. With standard therapies, MM remains incurable; therefore, the development of new drugs or immune cell-based therapies is desirable. To advance the goal of finding a more effective treatment for MM, we aimed to develop a reliable preclinical MM mouse model applying sensitive and reproducible methods for monitoring of tumor growth and metastasis in response to therapy. Material and Methods: A mouse model was created by intravenously injecting bone marrow-homing mouse myeloma cells (MOPC-315.BM) that expressed luciferase into BALB/c wild type mice. The luciferase in the myeloma cells allowed in vivo tracking before and after melphalan treatment with bioluminescence imaging (BLI). Homing of MOPC-315.BM luciferase+ myeloma cells to specific tissues was examined by flow cytometry. Idiotype-specific myeloma protein serum levels were measured by ELISA. In vivo measurements were validated with histopathology. Results: Strong bone marrow tropism and subsequent dissemination of MOPC-315.BM luciferase+ cells in vivo closely mimicked the human disease. In vivo BLI and later histopathological analysis revealed that 12 days of melphalan treatment slowed tumor progression and reduced MM dissemination compared to untreated controls. MOPC-315.BM luciferase+ cells expressed CXCR4 and high levels of CD44 and a4b1 in vitro which could explain the strong bone marrow tropism. The results showed that MOPC-315.BM cells dynamically regulated homing receptor expression and depended on interactions with surrounding cells. Conclusions: This study described a novel MM mouse model that facilitated convenient, reliable, and sensitive tracking of myeloma cells with whole body BLI in living animals. This model is highly suitable for monitoring the effects of different treatment regimens.},
  subject      = {Medizin},
  language  = {en}
}
@article{HorvatVogelKampfetal.2020,
  author    = {Horvat, Sonja and Vogel, Patrick and Kampf, Thomas and Brandl, Andreas and Alshamsan, Aws and Alhadlaq, Hisham A. and Ahamed, Maqusood and Albrecht, Krystyna and Behr, Volker C. and Beilhack, Andreas and Groll, J{\"u}rgen},
  title     = {Crosslinked Coating Improves the Signal-to-Noise Ratio of Iron Oxide Nanoparticles in Magnetic Particle Imaging (MPI)},
  series = {ChemNanoMat},
  volume    = {6},
  journal   = {ChemNanoMat},
  number    = {5},
  doi       = {10.1002/cnma.202000009},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-214718},
  pages     = {755 -- 758},
  year      = {2020},
  abstract  = {Magnetic particle imaging is an emerging tomographic method used for evaluation of the spatial distribution of iron-oxide nanoparticles. In this work, the effect of the polymer coating on the response of particles was studied. Particles with covalently crosslinked coating showed improved signal and image resolution.},
  language  = {en}
}
@article{ShaikhVargasMokhtarietal.2021,
  author    = {Shaikh, Haroon and Vargas, Juan Gamboa and Mokhtari, Zeinab and Jarick, Katja J. and Ulbrich, Maria and Mosca, Josefina Pe{\~n}a and Viera, Estibaliz Arellano and Graf, Caroline and Le, Duc-Dung and Heinze, Katrin G. and B{\"u}ttner-Herold, Maike and Rosenwald, Andreas and Pezoldt, Joern and Huehn, Jochen and Beilhack, Andreas},
  title     = {Mesenteric Lymph Node Transplantation in Mice to Study Immune Responses of the Gastrointestinal Tract},
  series = {Frontiers in Immunology},
  volume    = {12},
  journal   = {Frontiers in Immunology},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2021.689896},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-244869},
  year      = {2021},
  abstract  = {Mesenteric lymph nodes (mLNs) are sentinel sites of enteral immunosurveillance and immune homeostasis. Immune cells from the gastrointestinal tract (GIT) are constantly recruited to the mLNs in steady-state and under inflammatory conditions resulting in the induction of tolerance and immune cells activation, respectively. Surgical dissection and transplantation of lymph nodes (LN) is a technique that has supported seminal work to study LN function and is useful to investigate resident stromal and endothelial cell biology and their cellular interactions in experimental disease models. Here, we provide a detailed protocol of syngeneic mLN transplantation and report assays to analyze effective mLN engraftment in congenic recipients. Transplanted mLNs allow to study T cell activation and proliferation in preclinical mouse models. Donor mLNs proved viable and functional after surgical transplantation and regenerated blood and lymphatic vessels. Immune cells from the host completely colonized the transplanted mLNs within 7-8 weeks after the surgical intervention. After allogeneic hematopoietic cell transplantation (allo-HCT), adoptively transferred allogeneic CD4+ T cells from FVB/N (H-2q) mice homed to the transplanted mLNs in C57BL/6 (H-2b) recipients during the initiation phase of acute graft-versus-host disease (aGvHD). These CD4+ T cells retained full proliferative capacity and upregulated effector and gut homing molecules comparable to those in mLNs from unmanipulated wild-type recipients. Wild type mLNs transplanted into MHCII deficient syngeneic hosts sufficed to activate alloreactive T cells upon allogeneic hematopoietic cell transplantation, even in the absence of MHCII+ CD11c+ myeloid cells. These data support that orthotopically transplanted mLNs maintain physiological functions after transplantation. The technique of LN transplantation can be applied to study migratory and resident cell compartment interactions in mLNs as well as immune reactions from and to the gut under inflammatory and non-inflammatory conditions.},
  language  = {en}
}
@article{DahlhoffManzSteinfattetal.2022,
  author    = {Dahlhoff, Julia and Manz, Hannah and Steinfatt, Tim and Delgado-Tascon, Julia and Seebacher, Elena and Schneider, Theresa and Wilnit, Amy and Mokhtari, Zeinab and Tabares, Paula and B{\"o}ckle, David and Rasche, Leo and Martin Kort{\"u}m, K. and Lutz, Manfred B. and Einsele, Hermann and Brandl, Andreas and Beilhack, Andreas},
  title     = {Transient regulatory T-cell targeting triggers immune control of multiple myeloma and prevents disease progression},
  series = {Leukemia},
  volume    = {36},
  journal   = {Leukemia},
  number    = {3},
  issn      = {1476-5551},
  doi       = {10.1038/s41375-021-01422-y},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-271787},
  pages     = {790-800},
  year      = {2022},
  abstract  = {Multiple myeloma remains a largely incurable disease of clonally expanding malignant plasma cells. The bone marrow microenvironment harbors treatment-resistant myeloma cells, which eventually lead to disease relapse in patients. In the bone marrow, CD4\(^{+}\)FoxP3\(^{+}\) regulatory T cells (Tregs) are highly abundant amongst CD4\(^{+}\) T cells providing an immune protective niche for different long-living cell populations, e.g., hematopoietic stem cells. Here, we addressed the functional role of Tregs in multiple myeloma dissemination to bone marrow compartments and disease progression. To investigate the immune regulation of multiple myeloma, we utilized syngeneic immunocompetent murine multiple myeloma models in two different genetic backgrounds. Analyzing the spatial immune architecture of multiple myeloma revealed that the bone marrow Tregs accumulated in the vicinity of malignant plasma cells and displayed an activated phenotype. In vivo Treg depletion prevented multiple myeloma dissemination in both models. Importantly, short-term in vivo depletion of Tregs in mice with established multiple myeloma evoked a potent CD8 T cell- and NK cell-mediated immune response resulting in complete and stable remission. Conclusively, this preclinical in-vivo study suggests that Tregs are an attractive target for the treatment of multiple myeloma.},
  language  = {en}
}
@article{MajumderJugovicSauletal.2021,
  author    = {Majumder, Snigdha and Jugovic, Isabelle and Saul, Domenica and Bell, Luisa and Hundhausen, Nadine and Seal, Rishav and Beilhack, Andreas and Rosenwald, Andreas and Mougiakakos, Dimitrios and Berberich-Siebelt, Friederike},
  title     = {Rapid and Efficient Gene Editing for Direct Transplantation of Naive Murine Cas9\(^+\) T Cells},
  series = {Frontiers in Immunology},
  volume    = {12},
  journal   = {Frontiers in Immunology},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2021.683631},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-242896},
  year      = {2021},
  abstract  = {Gene editing of primary T cells is a difficult task. However, it is important for research and especially for clinical T-cell transfers. CRISPR/Cas9 is the most powerful gene-editing technique. It has to be applied to cells by either retroviral transduction or electroporation of ribonucleoprotein complexes. Only the latter is possible with resting T cells. Here, we make use of Cas9 transgenic mice and demonstrate nucleofection of pre-stimulated and, importantly, of naive CD3\(^+\) T cells with guideRNA only. This proved to be rapid and efficient with no need of further selection. In the mixture of Cas9\(^+\)CD3\(^+\) T cells, CD4\(^+\) and CD8\(^+\) conventional as well as regulatory T cells were targeted concurrently. IL-7 supported survival and naivety in vitro, but T cells were also transplantable immediately after nucleofection and elicited their function like unprocessed T cells. Accordingly, metabolic reprogramming reached normal levels within days. In a major mismatch model of GvHD, not only ablation of NFATc1 and/or NFATc2, but also of the NFAT-target gene IRF4 in na{\"i}ve primary murine Cas9\(^+\)CD3\(^+\) T cells by gRNA-only nucleofection ameliorated GvHD. However, pre-activated murine T cells could not achieve long-term protection from GvHD upon single NFATc1 or NFATc2 knockout. This emphasizes the necessity of gene-editing and transferring unstimulated human T cells during allogenic hematopoietic stem cell transplantation.},
  language  = {en}
}
@article{RudeliusRosenfeldtLeichetal.2019,
  author    = {Rudelius, Martina and Rosenfeldt, Mathias Tillmann and Leich, Ellen and Rauert-Wunderlich, Hilka and Solimando, Antonio Giovanni and Ott, German and Rosenwald, Andreas and Beilhack, Andreas},
  title     = {Inhibition of focal adhesion kinase overcomes resistance of mantle cell lymphoma to ibrutinib in the bone marrow microenvironment},
  series = {Haematologica},
  volume    = {103},
  journal   = {Haematologica},
  number    = {1},
  doi       = {10.3324/haematol.2017.177162},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227117},
  pages     = {116-125},
  year      = {2019},
  abstract  = {Mantle cell lymphoma and other lymphoma subtypes often spread to the bone marrow, and stromal interactions mediated by focal adhesion kinase frequently enhance survival and drug resistance of the lymphoma cells. To study the role of focal adhesion kinase in mantle cell lymphoma, immunohistochemistry of primary cases and functional analysis of mantle cell lymphoma cell lines and primary mantle cell lymphoma cells co-cultured with bone marrow stromal cells (BMSC) using small molecule inhibitors and RNAi-based focal adhesion kinase silencing was performed. We showed that focal adhesion kinase is highly expressed in bone marrow infiltrates of mantle cell lymphoma and in mantle cell lymphoma cell lines. Stroma-mediated activation of focal adhesion kinase led to activation of multiple kinases (AKT, p42/44 and NF-kappa B), that are important for prosurvival and proliferation signaling. Interestingly, RNAi-based focal adhesion kinase silencing or inhibition with small molecule inhibitors (FAKi) resulted in blockage of targeted cell invasion and induced apoptosis by inactivation of multiple signaling cascades, including the classic and alternative NF-kappa B pathway. In addition, the combined treatment of ibrutinib and FAKi was highly synergistic, and ibrutinib resistance of mantle cell lymphoma could be overcome. These data demonstrate that focal adhesion kinase is important for stroma-mediated survival and drug resistance in mantle cell lymphoma, providing indications for a targeted therapeutic strategy.},
  subject      = {Multiple},
  language  = {en}
}