TY  - JOUR
A1  - Dahlhoff, Julia
A1  - Manz, Hannah
A1  - Steinfatt, Tim
A1  - Delgado-Tascon, Julia
A1  - Seebacher, Elena
A1  - Schneider, Theresa
A1  - Wilnit, Amy
A1  - Mokhtari, Zeinab
A1  - Tabares, Paula
A1  - Böckle, David
A1  - Rasche, Leo
A1  - Martin Kortüm, K.
A1  - Lutz, Manfred B.
A1  - Einsele, Hermann
A1  - Brandl, Andreas
A1  - Beilhack, Andreas
T1  - Transient regulatory T-cell targeting triggers immune control of multiple myeloma and prevents disease progression
JF  - Leukemia
N2  - 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.
KW  - Multiple myeloma
KW  - transient regulatory T-cell targeting
KW  - immune control
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-271787
SN  - 1476-5551
VL  - 36
IS  - 3
ER  - 
TY  - JOUR
A1  - Dotterweich, Julia
A1  - Tower, Robert J.
A1  - Brandl, Andreas
A1  - Müller, Marc
A1  - Hofbauer, Lorenz C.
A1  - Beilhack, Andreas
A1  - Ebert, Regina
A1  - Glüer, Claus C.
A1  - Tiwari, Sanjay
A1  - Schütze, Norbert
A1  - Jakob, Franz
T1  - The KISS1 Receptor as an In Vivo Microenvironment Imaging Biomarker of Multiple Myeloma Bone Disease
JF  - PLoS One
N2  - 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.
KW  - multiple myeloma Lesions
KW  - fluorescence microscopy
KW  - biomarkers Myelomas
KW  - bone imaging
KW  - myeloma cells
KW  - fluorescent dyes
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146960
VL  - 11
IS  - 5
ER  - 
TY  - JOUR
A1  - Chopra, Martin
A1  - Biehl, Marlene
A1  - Steinfatt, Tim
A1  - Brandl, Andreas
A1  - Kums, Juliane
A1  - Amich, Jorge
A1  - Vaeth, Martin
A1  - Kuen, Janina
A1  - Holtappels, Rafaela
A1  - Podlech, Jürgen
A1  - Mottok, Anja
A1  - Kraus, Sabrina
A1  - Jordán-Garotte, Ana-Laura
A1  - Bäuerlein, Carina A.
A1  - Brede, Christian
A1  - Ribechini, Eliana
A1  - Fick, Andrea
A1  - Seher, Axel
A1  - Polz, Johannes
A1  - Ottmueller, Katja J.
A1  - Baker, Jeannette
A1  - Nishikii, Hidekazu
A1  - Ritz, Miriam
A1  - Mattenheimer, Katharina
A1  - Schwinn, Stefanie
A1  - Winter, Thorsten
A1  - Schäfer, Viktoria
A1  - Krappmann, Sven
A1  - Einsele, Hermann
A1  - Müller, Thomas D.
A1  - Reddehase, Matthias J.
A1  - Lutz, Manfred B.
A1  - Männel, Daniela N.
A1  - Berberich-Siebelt, Friederike
A1  - Wajant, Harald
A1  - Beilhack, Andreas
T1  - Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion
JF  - Journal of Experimental Medicine
N2  - 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.
KW  - Tumor-necrosis-factor
KW  - Regulatory-cells
KW  - Bone marrow transplantantation
KW  - Graft-versus-leukemia
KW  - Rheumatoid arthritis
KW  - Autoimmune diseases
KW  - Factor receptor
KW  - Alpha therapy
KW  - Expression
KW  - Suppression
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187640
VL  - 213
IS  - 9
ER  - 
TY  - JOUR
A1  - Horvat, Sonja
A1  - Vogel, Patrick
A1  - Kampf, Thomas
A1  - Brandl, Andreas
A1  - Alshamsan, Aws
A1  - Alhadlaq, Hisham A.
A1  - Ahamed, Maqusood
A1  - Albrecht, Krystyna
A1  - Behr, Volker C.
A1  - Beilhack, Andreas
A1  - Groll, Jürgen
T1  - Crosslinked Coating Improves the Signal‐to‐Noise Ratio of Iron Oxide Nanoparticles in Magnetic Particle Imaging (MPI)
JF  - ChemNanoMat
N2  - 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.
KW  - crosslinked coating
KW  - imaging agents
KW  - magnetic properties
KW  - MPI
KW  - MPS
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-214718
VL  - 6
IS  - 5
SP  - 755
EP  - 758
ER  - 
TY  - JOUR
A1  - Rath, Subha N.
A1  - Brandl, Andreas
A1  - Hiller, Daniel
A1  - Hoppe, Alexander
A1  - Gbureck, Uwe
A1  - Horch, Raymund E.
A1  - Boccaccini, Aldo R.
A1  - Kneser, Ulrich
T1  - Bioactive Copper-Doped Glass Scaffolds Can Stimulate Endothelial Cells in Co-Culture in Combination with Mesenchymal Stem Cells
JF  - PLOS ONE
N2  - Bioactive glass (BG) scaffolds are being investigated for bone tissue engineering applications because of their osteoconductive and angiogenic nature. However, to increase the in vivo performance of the scaffold, including enhancing the angiogenetic growth into the scaffolds, some researchers use different modifications of the scaffold including addition of inorganic ionic components to the basic BG composition. In this study, we investigated the in vitro biocompatibility and bioactivity of Cu2+-doped BG derived scaffolds in either BMSC (bone-marrow derived mesenchymal stem cells)-only culture or co-culture of BMSC and human dermal microvascular endothelial cells (HDMEC). In BMSC-only culture, cells were seeded either directly on the scaffolds (3D or direct culture) or were exposed to ionic dissolution products of the BG scaffolds, kept in permeable cell culture inserts (2D or indirect culture). Though we did not observe any direct osteoinduction of BMSCs by alkaline phosphatase (ALP) assay or by PCR, there was increased vascular endothelial growth factor (VEGF) expression, observed by PCR and ELISA assays. Additionally, the scaffolds showed no toxicity to BMSCs and there were healthy live cells found throughout the scaffold. To analyze further the reasons behind the increased VEGF expression and to exploit the benefits of the finding, we used the indirect method with HDMECs in culture plastic and Cu2+-doped BG scaffolds with or without BMSCs in cell culture inserts. There was clear observation of increased endothelial markers by both FACS analysis and acetylated LDL (acLDL) uptake assay. Only in presence of Cu2+-doped BG scaffolds with BMSCs, a high VEGF secretion was demonstrated by ELISA; and typical tubular structures were observed in culture plastics. We conclude that Cu2+-doped BG scaffolds release Cu2+, which in turn act on BMSCs to secrete VEGF. This result is of significance for the application of BG scaffolds in bone tissue engineering approaches.
KW  - arteriovenous loop
KW  - calcium-phosphate
KW  - iron release
KW  - bone
KW  - angiogenesis
KW  - expression
KW  - differentation
KW  - proliferation
KW  - osteoblasts
KW  - growth
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-114339
SN  - 1932-6203
VL  - 9
IS  - 12
ER  -