21 results on '"Riesner, Katarina"'
Search Results
2. Initiation of acute graft-versus-host disease by angiogenesis
- Author
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Riesner, Katarina, Shi, Yu, Jacobi, Angela, Kräter, Martin, Kalupa, Martina, McGearey, Aleixandria, Mertlitz, Sarah, Cordes, Steffen, Schrezenmeier, Jens-Florian, Mengwasser, Jörg, Westphal, Sabine, Perez-Hernandez, Daniel, Schmitt, Clemens, Dittmar, Gunnar, Guck, Jochen, and Penack, Olaf
- Published
- 2017
- Full Text
- View/download PDF
3. Lymphangiogenesis is a feature of acute GVHD, and VEGFR-3 inhibition protects against experimental GVHD
- Author
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Mertlitz, Sarah, Shi, Yu, Kalupa, Martina, Grötzinger, Carsten, Mengwasser, Jörg, Riesner, Katarina, Cordes, Steffen, Elezkurtaj, Sefer, and Penack, Olaf
- Published
- 2017
- Full Text
- View/download PDF
4. Inflammatory neovascularization during graft-versus-host disease is regulated by αv integrin and miR-100
- Author
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Leonhardt, Franziska, Grundmann, Sebastian, Behe, Martin, Bluhm, Franziska, Dumont, Rebecca A., Braun, Friederike, Fani, Melpomeni, Riesner, Katarina, Prinz, Gabriele, Hechinger, Anne-Kathrin, Gerlach, Ulrike V., Dierbach, Heide, Penack, Olaf, Schmitt-Gräff, Annette, Finke, Jürgen, Weber, Wolfgang A., and Zeiser, Robert
- Published
- 2013
- Full Text
- View/download PDF
5. Endothelial damage and dysfunction in acute graft-versus-host disease
- Author
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Cordes, Steffen, Mokhtari, Zeinab, Bartosova, Maria, Mertlitz, Sarah, Riesner, Katarina, Shi, Yu, Mengwasser, Jörg, Kalupa, Martina, McGeary, Aleixandria, Schleifenbaum, Johanna, Schrezenmeier, Jens, Bullinger, Lars, Diaz-Ricart, Maribel, Palomo, Marta, Carreras, Enric, Beutel, Gernot, Schmitt, Claus Peter, Beilhack, Andreas, Penack, Olaf, and Universitat Autònoma de Barcelona
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Sildenafil ,T-Lymphocytes ,Graft vs Host Disease ,Disease ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Acute graft versus host disease ,medicine ,Animals ,Humans ,Endothelium ,Endothelial dysfunction ,Tight junction ,integumentary system ,business.industry ,Endothelial Cells ,Hematology ,medicine.disease ,In vitro ,Graft-versus-host disease ,surgical procedures, operative ,chemistry ,Cardiovascular and Metabolic Diseases ,Apoptosis ,Steroids ,business ,030215 immunology - Abstract
Altres ajuts: Deutsche Forschungsgemeinschaft (DFG) TRR221 (B11 Z02), TRR225 (B08) Clinical studies have suggested a potential involvement of endothelial dysfunction and damage in the development and severity of acute graft-versus-host disease (aGvHD). Accordingly, we found an increased percentage of apoptotic caspase 3 positive blood vessels in duodenal and colonic mucosa biopsies of patients with severe aGvHD. In murine experimental aGvHD, we detected severe microstructural endothelial damage and reduced endothelial pericyte coverage accompanied by reduced expression of endothelial tight junction proteins leading to increased endothelial leakage in aGvHD target organs. During intestinal aGvHD, colonic vasculature structurally changed, reflected by increased vessel branching and vessel diameter. As recent data demonstrated an association of endothelium-related factors and steroid refractory aGvHD (SR-aGvHD), we analyzed human biopsies and murine tissues from SR-aGvHD. We found extensive tissue damage but low levels of alloreactive T-cell infiltration in target organs, providing the rationale for T-cell independent SR-aGvHD treatment strategies. Consequently, we tested the endothelium-protective PDE5 inhibitor sildenafil, which reduced apoptosis and improved metabolic activity of endothelial cells in vitro. Accordingly, sildenafil treatment improved survival and reduced target organ damage during experimental SR-aGvHD. Our results demonstrate extensive damage, structural changes, and dysfunction of the vasculature during aGvHD. Therapeutic intervention by endothelium-protecting agents is an attractive approach for SR-aGvHD complementing current anti-inflammatory treatment options.
- Published
- 2020
6. Novel pre-clinical mouse models for chronic Graftversus-Host Disease.
- Author
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Verlaat, Lydia, Riesner, Katarina, Kalupa, Martina, Jung, Beate, Mertlitz, Sarah, Schwarz, Constanze, Mengwasser, Jörg, Frick, Claudine, and Penack, Olaf
- Abstract
Despite considerable progress in allogeneic hematopoietic cell transplantation (allo-HCT) has been achieved over the past years, chronic Graft-versus-Host Disease (cGvHD) still contributes to high morbidity rates, thus remaining a major hurdle in allo-HCT patients. To understand the complex pathophysiology of cGvHD and to develop refined prophylaxis and treatment strategies, improved pre-clinical models are needed. In this study, we developed two murine cGvHD models, which display high long-term morbidity but low mortality and depict the heterogeneous clinical manifestations of cGvHD seen in patients. We established a haploidentical C57BL/6!B6D2F1 allo-HCT model that uses myeloablative radiation and GCSF-mobilized splenocytes as stem cell source and a sub-lethally irradiated Xenograft model, which utilizes the transfer of human peripheral blood mononuclear cells (PBMCs) into NOD scid gamma (NSG)-recipients. We characterized both mouse models to exhibit diverse clinical and histopathological signs of human cGvHD as extensive tissue damage, fibrosis/sclerosis, inflammation and B cell infiltration in cGvHD target organs skin, liver, lung and colon and found a decelerated immune cell reconstitution in the late phase after HCT. Our pre-clinical models can help to gain a deeper understanding of the target structures and mechanisms of cGvHD pathology and may enable a more reliable translation of experimental findings into the human setting of allo-HCT. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
7. Reduced Calcium Signaling Is Associated With Severe Graft-Versus-Host Disease: Results From Preclinical Models and From a Prospective EBMT Study
- Author
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Riesner, Katarina, Cordes, Steffen, Peczynski, Christophe, Kalupa, Martina, Schwarz, Constanze, Shi, Yu, Mertlitz, Sarah, Mengwasser, Jörg, van der Werf, Steffie, Peric, Zinaida, Koenecke, Christian, Schoemans, Helene, Duarte, Rafael F., Basak, Grzegorz W., and Penack, Olaf
- Subjects
GPRC6a ,Immunology ,Graft vs Host Disease ,Mice, Transgenic ,ACUTE GVHD ,stem cell transplantation ,Immunophenotyping ,Receptors, G-Protein-Coupled ,graft-versus-host-disease ,Recurrence ,Leukocytes ,Animals ,Transplantation, Homologous ,Calcium Signaling ,Original Research ,Mice, Knockout ,GVHD mouse models ,EBMT study ,Science & Technology ,calcium ,GPRC6A ,RECEPTOR ,Incidence ,Hematopoietic Stem Cell Transplantation ,Prognosis ,Disease Models, Animal ,surgical procedures, operative ,Calcium ,Female ,Disease Susceptibility ,Life Sciences & Biomedicine ,600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit ,Biomarkers - Abstract
Despite its involvement in various immune functions, including the allogeneic activation of T-lymphocytes, the relevance of calcium (Ca2+) for GVHD pathobiology is largely unknown. To elucidate a potential association between Ca2+and GVHD, we analyzed Ca2+-sensing G-protein coupled receptor 6a (GPRC6a) signaling in preclinical GVHD models and conducted a prospective EBMT study on Ca2+ serum levels prior alloSCT including 363 matched sibling allogeneic peripheral blood stem cell transplantations (alloSCTs). In experimental models, we found decreased Gprc6a expression during intestinal GVHD. GPRC6a deficient alloSCT recipients had higher clinical and histopathological GVHD scores leading to increased mortality. As possible underlying mechanism, we found increased antigen presentation potential in GPRC6a-/- alloSCT recipients demonstrated by higher proliferation rates of T-lymphocytes. In patients with low Ca2+ serum levels (≤median 2.2 mmol/l) before alloSCT, we found a higher incidence of acute GVHD grades II-IV (HR = 2.3 Cl = 1.45-3.85 p = 0.0006), severe acute GVHD grades III-IV (HR = 3.3 CI = 1.59-7.14, p = 0.002) and extensive chronic GVHD (HR = 2.0 Cl = 1.04-3.85 p = 0.04). In conclusion, experimental and clinical data suggest an association of reduced Ca2+ signaling with increased severity of GVHD. Future areas of interest include the in depth analysis of involved molecular pathways and the investigation of Ca2+ signaling as a therapeutic target during GVHD. ispartof: FRONTIERS IN IMMUNOLOGY vol:11 ispartof: location:Switzerland status: published
- Published
- 2020
8. Fibroblast growth factor receptor 1 gene amplification in pancreatic ductal adenocarcinoma
- Author
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Lehnen, Nils C, von Mässenhausen, Anne, Kalthoff, Holger, Zhou, Hui, Glowka, Tim, Schütte, Ute, Höller, Tobias, Riesner, Katarina, Boehm, Diana, Merkelbach-Bruse, Sabine, Kirfel, Jutta, Perner, Sven, and Gütgemann, Ines
- Published
- 2013
- Full Text
- View/download PDF
9. TRAIL receptor I (DR4) polymorphisms C626G and A683C are associated with an increased risk for hepatocellular carcinoma (HCC) in HCV-infected patients
- Author
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Körner Christian, Riesner Katarina, Krämer Benjamin, Eisenhardt Marianne, Glässner Andreas, Wolter Franziska, Berg Thomas, Müller Tobias, Sauerbruch Tilman, Nattermann Jacob, Spengler Ulrich, and Nischalke Hans
- Subjects
TRAIL receptor I ,DR4 ,Apoptosis ,Polymorphism ,C626G (rs20575) ,A683C (rs20576) ,HCV ,HCC ,Cancer ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Tumour surveillance via induction of TRAIL-mediated apoptosis is a key mechanism, how the immune system prevents malignancy. To determine if gene variants in the TRAIL receptor I (DR4) gene affect the risk of hepatitis C virus (HCV)-induced liver cancer (HCC), we analysed DR4 mutations C626G (rs20575) and A683C (rs20576) in HCV-infected patients with and without HCC. Methods Frequencies of DR4 gene polymorphisms were determined by LightSNiP assays in 159 and 234 HCV-infected patients with HCC and without HCC, respectively. 359 healthy controls served as reference population. Results Distribution of C626G and A683C genotypes were not significantly different between healthy controls and HCV-positive patients without HCC. DR4 variants 626C and 683A occurred at increased frequencies in patients with HCC. The risk of HCC was linked to carriage of the 626C allele and the homozygous 683AA genotype, and the simultaneous presence of the two risk variants was confirmed as independent HCC risk factor by Cox regression analysis (Odds ratio 1.975, 95% CI 1.205-3.236; p = 0.007). Furthermore HCV viral loads were significantly increased in patients who simultaneously carried both genetic risk factors (2.69 ± 0.36 × 106 IU/ml vs. 1.81 ± 0.23 × 106 IU/ml, p = 0.049). Conclusions The increased prevalence of patients with a 626C allele and the homozygous 683AA genotype in HCV-infected patients with HCC suggests that these genetic variants are a risk factor for HCC in chronic hepatitis C.
- Published
- 2012
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- View/download PDF
10. Acute Graft-vs.-Host Disease-Associated Endothelial Activation in vitro Is Prevented by Defibrotide.
- Author
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Martinez-Sanchez, Julia, Hamelmann, Hannah, Palomo, Marta, Mir, Enrique, Moreno-Castaño, Ana Belen, Torramade, Sergi, Rovira, Montserrat, Escolar, Ginés, Cordes, Steffen, Kalupa, Martina, Mertlitz, Sarah, Riesner, Katarina, Carreras, Enric, Penack, Olaf, and Diaz-Ricart, Maribel
- Subjects
HEPATIC veno-occlusive disease ,VASCULAR cell adhesion molecule-1 ,CD54 antigen ,CADHERINS ,CELL adhesion molecules ,PHARMACOLOGY ,VON Willebrand factor ,ENDOTHELIUM diseases - Abstract
Angiogenesis and endothelial activation and dysfunction have been associated with acute graft-vs.-host disease (aGVHD), pointing to the endothelium as a potential target for pharmacological intervention. Defibrotide (DF) is a drug with an endothelium-protective effect that has been approved for the treatment of veno-occlusive disease/sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation. Clinical data suggest that DF also reduces the incidence of aGVHD; however, the mechanisms of DF-mediated aGVHD regulation have not been examined. To investigate possible DF-mediated prophylactic and therapeutic mechanisms in aGVHD, we performed in vitro studies using endothelial cell (EC) lines. We found that DF significantly and dose-dependently suppressed EC proliferation and notably reduced their ability to form vascular tubes in Matrigel. To explore whether DF administered prophylactically or therapeutically has a significant effect on aGVHD endothelial dysfunction, ECs were exposed to media containing sera from patients with aGVHD (n = 22) in the absence or presence of DF and from patients that did not develop aGVHD (n = 13). ECs upregulated adhesion molecules (vascular cell adhesion molecule 1, intercellular adhesion molecule 1), the adherence junction protein VE-cadherin, von Willebrand factor (VWF), and Akt phosphorylation in response to aGVHD sera. These responses were suppressed upon treatment with DF. In summary, DF inhibits vascular angiogenesis and endothelial activation induced by sera from aGVHD patients. Our results support the view that DF has notable positive effects on endothelial biology during aGVHD. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
11. Cathepsin E Deficiency Ameliorates Graft-versus-Host Disease and Modifies Dendritic Cell Motility.
- Author
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Mengwasser, Jörg, Babes, Liane, Cordes, Steffen, Mertlitz, Sarah, Riesner, Katarina, Yu Shi, McGearey, Aleixandria, Kalupa, Martina, Reinheckel, Thomas, and Penack, Olaf
- Subjects
CATHEPSINS ,GRAFT versus host disease ,DENDRITIC cells - Abstract
Microbial products influence immunity after allogeneic hematopoietic stem cell transplantation (allo-SCT). In this context, the role of cathepsin E (Ctse), an aspartate protease known to cleave bacterial peptides for antigen presentation in dendritic cells (DCs), has not been studied. During experimental acute graft-versus-host disease (GVHD), we found infiltration by Ctse-positive immune cells leading to higher Ctse RNA- and protein levels in target organs. In Ctse-deficient allo-SCT recipients, we found ameliorated GVHD, improved survival, and lower numbers of tissue-infiltrating DCs. Donor T cell proliferation was not different in Ctse-deficient vs. wild-type allo-SCT recipients in MHC-matched and MHC-mismatched models. Furthermore, Ctse-deficient DCs had an intact ability to induce allogeneic T cell proliferation, suggesting that its role in antigen presentation may not be the main mechanism how Ctse impacts GVHD. We found that Ctse deficiency significantly decreases DC motility in vivo, reduces adhesion to extracellular matrix (ECM), and diminishes invasion through ECM. We conclude that Ctse has a previously unrecognized role in regulating DC motility that possibly contributes to reduced DC counts and ameliorated inflammation in GVHD target organs of Ctse-deficient allo-SCT recipients. However, our data do not provide definite proof that the observed effect of Ctse
-/- deficiency is exclusively mediated by DCs. A contribution of Ctse-/- -mediated functions in other recipient cell types, e.g., macrophages, cannot be excluded. [ABSTRACT FROM AUTHOR]- Published
- 2017
- Full Text
- View/download PDF
12. Initiation of Acute Graft-Versus-Host Disease By Angiogenesis
- Author
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Riesner, Katarina, Shi, Yu, Jacobi, Angela, Kraeter, Martin, Kalupa, Martina, McGearey, Aleixandria, Mertlitz, Sarah, Cordes, Steffen, Schrezenmeier, Jens-Florian, Mengwasser, Joerg, Westphal, Sabine, Perez-Hernandez, Daniel, Schmitt, Clemens, Dittmar, Gunnar, Guck, Jochen, and Penack, Olaf
- Published
- 2016
- Full Text
- View/download PDF
13. Ocular Graft-versus-Host Disease in a Chemotherapy-Based Minor-Mismatch Mouse Model Features Corneal (Lymph-) Angiogenesis.
- Author
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Gehlsen, Uta, Stary, Daniela, Maass, Martina, Riesner, Katarina, Musial, Gwen, Stern, Michael E., Penack, Olaf, and Steven, Philipp
- Subjects
LABORATORY mice ,GRAFT versus host disease ,CORNEA ,HEMATOPOIETIC stem cell transplantation ,NEOVASCULARIZATION ,THERAPEUTICS - Abstract
Ocular graft-versus-host disease (oGVHD) is a fast progressing, autoimmunological disease following hematopoietic stem cell transplantation, leading to severe inflammation of the eye and destruction of the lacrimal functional unit with consecutive sight-threatening consequences. The therapeutic "window of opportunity" is narrow, and current treatment options are limited and often insufficient. To achieve new insights into the pathogenesis and to develop new therapeutic approaches, clinically relevant models of oGVHD are desirable. In this study, the ocular phenotype was described in a murine, chemotherapy-based, minor-mismatch GVHD model mimicking early-onset chronic oGVHD, with corneal epitheliopathy, inflammation of the lacrimal glands, and blepharitis. Additionally, corneal lymphangiogenesis was observed as part of oGVHD pathogenesis for the first time, thus opening up the investigation of lymphangiogenesis as a potential therapeutic and diagnostic tool. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
14. Spatio-Temporal Bone Remodeling after Hematopoietic Stem Cell Transplantation.
- Author
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Schwarz, Constanze S., Bucher, Christian H., Schlundt, Claudia, Mertlitz, Sarah, Riesner, Katarina, Kalupa, Martina, Verlaat, Lydia, Schmidt-Bleek, Oskar, Sass, Radost A., Schmidt-Bleek, Katharina, Duda, Georg N., Penack, Olaf, and Na, Il-Kang
- Subjects
HEMATOPOIETIC stem cell transplantation ,BONE remodeling ,BONE marrow cells ,T cells ,COMPACT bone ,BONE cells ,HEMATOPOIETIC stem cells - Abstract
The interaction of hematopoietic cells and the bone microenvironment to maintain bone homeostasis is increasingly appreciated. We hypothesized that the transfer of allogeneic T lymphocytes has extensive effects on bone biology and investigated trabecular and cortical bone structures, the osteoblast reconstitution, and the bone vasculature in experimental hematopoietic stem cell transplantations (HSCT). Allogeneic or syngeneic hematopoietic stem cells (HSC) and allogeneic T lymphocytes were isolated and transferred in a murine model. After 20, 40, and 60 days, bone structures were visualized using microCT and histology. Immune cells were monitored using flow cytometry and bone vessels, bone cells and immune cells were fluorescently stained and visualized. Remodeling of the bone substance, the bone vasculature and bone cell subsets were found to occur as early as day +20 after allogeneic HSCT (including allogeneic T lymphocytes) but not after syngeneic HSCT. We discovered that allogeneic HSCT (including allogeneic T lymphocytes) results in a transient increase of trabecular bone number and bone vessel density. This was paralleled by a cortical thinning as well as disruptive osteoblast lining and loss of B lymphocytes. In summary, our data demonstrate that the adoptive transfer of allogeneic HSCs and allogeneic T lymphocytes can induce profound structural and spatial changes of bone tissue homeostasis as well as bone marrow cell composition, underlining the importance of the adaptive immune system for maintaining a balanced bone biology. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
15. The Global Evolution and Impact of Systems Biology and Artificial Intelligence in Stem Cell Research and Therapeutics Development: A Scoping Review.
- Author
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Silva-Sousa T, Usuda JN, Al-Arawe N, Frias F, Hinterseher I, Catar R, Luecht C, Riesner K, Hackel A, Schimke LF, Dias HD, Filgueiras IS, Nakaya HI, Camara NOS, Fischer S, Riemekasten G, Ringdén O, Penack O, Winkler T, Duda G, Fonseca DLM, Cabral-Marques O, and Moll G
- Abstract
Advanced bioinformatics analysis, such as systems biology (SysBio) and artificial intelligence (AI) approaches, including machine learning (ML) and deep learning (DL), is increasingly present in stem cell (SC) research. An approximate timeline on these developments and their global impact is still lacking. We conducted a scoping review on the contribution of SysBio and AI analysis to SC research and therapy development based on literature published in PubMed between 2000 and 2024. We identified an 8-10-fold increase in research output related to all three search terms between 2000 and 2021, with a 10-fold increase in AI-related production since 2010. Use of SysBio and AI still predominates in preclinical basic research with increasing use in clinically oriented translational medicine since 2010. SysBio- and AI-related research was found all over the globe, with SysBio output led by the United States (US, n=1487), United Kingdom (UK, n=1094), Germany (n=355), The Netherlands (n=339), Russia (n=215), and France (n=149), while for AI-related research the US (n=853) and UK (n=258) take a strong lead, followed by Switzerland (n=69), The Netherlands (n=37), and Germany (n=19). The US and UK are most active in SCs publications related to AI/ML and AI/DL. The prominent use of SysBio in ESC research was recently overtaken by prominent use of AI in iPSC and MSC research. This study reveals the global evolution and growing intersection between AI, SysBio, and SC research over the past two decades, with substantial growth in all three fields and exponential increases in AI-related research in the past decade., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
- Published
- 2024
- Full Text
- View/download PDF
16. Novel pre-clinical mouse models for chronic Graft-versus-Host Disease.
- Author
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Verlaat L, Riesner K, Kalupa M, Jung B, Mertlitz S, Schwarz C, Mengwasser J, Fricke C, and Penack O
- Subjects
- Humans, Mice, Animals, Leukocytes, Mononuclear pathology, Transplantation, Homologous adverse effects, Mice, Inbred C57BL, Bronchiolitis Obliterans Syndrome, Graft vs Host Disease
- Abstract
Despite considerable progress in allogeneic hematopoietic cell transplantation (allo-HCT) has been achieved over the past years, chronic Graft-versus-Host Disease (cGvHD) still contributes to high morbidity rates, thus remaining a major hurdle in allo-HCT patients. To understand the complex pathophysiology of cGvHD and to develop refined prophylaxis and treatment strategies, improved pre-clinical models are needed. In this study, we developed two murine cGvHD models, which display high long-term morbidity but low mortality and depict the heterogeneous clinical manifestations of cGvHD seen in patients. We established a haploidentical C57BL/6→B6D2F1 allo-HCT model that uses myeloablative radiation and G-CSF-mobilized splenocytes as stem cell source and a sub-lethally irradiated Xenograft model, which utilizes the transfer of human peripheral blood mononuclear cells (PBMCs) into NOD scid gamma (NSG)-recipients. We characterized both mouse models to exhibit diverse clinical and histopathological signs of human cGvHD as extensive tissue damage, fibrosis/sclerosis, inflammation and B cell infiltration in cGvHD target organs skin, liver, lung and colon and found a decelerated immune cell reconstitution in the late phase after HCT. Our pre-clinical models can help to gain a deeper understanding of the target structures and mechanisms of cGvHD pathology and may enable a more reliable translation of experimental findings into the human setting of allo-HCT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Verlaat, Riesner, Kalupa, Jung, Mertlitz, Schwarz, Mengwasser, Fricke and Penack.)
- Published
- 2023
- Full Text
- View/download PDF
17. Endothelial damage and dysfunction in acute graft-versus-host disease.
- Author
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Cordes S, Mokhtari Z, Bartosova M, Mertlitz S, Riesner K, Shi Y, Mengwasser J, Kalupa M, McGeary A, Schleifenbaum J, Schrezenmeier J, Bullinger L, Diaz-Ricart M, Palomo M, Carrreras E, Beutel G, Schmitt CP, Beilhack A, and Penack O
- Subjects
- Animals, Endothelial Cells, Endothelium, Humans, Mice, Steroids, T-Lymphocytes, Graft vs Host Disease drug therapy, Graft vs Host Disease etiology
- Abstract
Clinical studies suggested that endothelial dysfunction and damage could be involved in the development and severity of acute graft-versus-host disease (aGVHD). Accordingly, we found increased percentage of apoptotic Casp3+ blood vessels in duodenal and colonic mucosa biopsies of patients with severe aGVHD. In murine experimental aGVHD, we detected severe microstructural endothelial damage and reduced endothelial pericyte coverage accompanied by reduced expression of endothelial tight junction proteins leading to increased endothelial leakage in aGVHD target organs. During intestinal aGVHD, colonic vasculature structurally changed, reflected by increased vessel branching and vessel diameter. Because recent data demonstrated an association of endothelium-related factors and steroid refractory aGVHD (SR-aGVHD), we analyzed human biopsies and murine tissues from SR-aGVHD. We found extensive tissue damage but low levels of alloreactive T cell infiltration in target organs, providing the rationale for T-cell independent SR-aGVHD treatment strategies. Consequently, we tested the endothelium-protective PDE5 inhibitor sildenafil, which reduced apoptosis and improved metabolic activity of endothelial cells in vitro. Accordingly, sildenafil treatment improved survival and reduced target organ damage during experimental SR-aGVHD. Our results demonstrate extensive damage, structural changes, and dysfunction of the vasculature during aGVHD. Therapeutic intervention by endothelium-protecting agents is an attractive approach for SR-aGVHD complementing current anti-inflammatory treatment options.
- Published
- 2021
- Full Text
- View/download PDF
18. Spatio-Temporal Bone Remodeling after Hematopoietic Stem Cell Transplantation.
- Author
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Schwarz CS, Bucher CH, Schlundt C, Mertlitz S, Riesner K, Kalupa M, Verlaat L, Schmidt-Bleek O, Sass RA, Schmidt-Bleek K, Duda GN, Penack O, and Na IK
- Subjects
- Animals, Biomarkers, Bone Marrow metabolism, Bone Marrow pathology, Diaphyses, Graft vs Host Disease etiology, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation methods, Immunophenotyping, Mice, Osteoblasts immunology, Osteoblasts metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism, Transplantation Chimera, Transplantation, Homologous, Bone Marrow Cells metabolism, Bone Remodeling
- Abstract
The interaction of hematopoietic cells and the bone microenvironment to maintain bone homeostasis is increasingly appreciated. We hypothesized that the transfer of allogeneic T lymphocytes has extensive effects on bone biology and investigated trabecular and cortical bone structures, the osteoblast reconstitution, and the bone vasculature in experimental hematopoietic stem cell transplantations (HSCT). Allogeneic or syngeneic hematopoietic stem cells (HSC) and allogeneic T lymphocytes were isolated and transferred in a murine model. After 20, 40, and 60 days, bone structures were visualized using microCT and histology. Immune cells were monitored using flow cytometry and bone vessels, bone cells and immune cells were fluorescently stained and visualized. Remodeling of the bone substance, the bone vasculature and bone cell subsets were found to occur as early as day +20 after allogeneic HSCT (including allogeneic T lymphocytes) but not after syngeneic HSCT. We discovered that allogeneic HSCT (including allogeneic T lymphocytes) results in a transient increase of trabecular bone number and bone vessel density. This was paralleled by a cortical thinning as well as disruptive osteoblast lining and loss of B lymphocytes. In summary, our data demonstrate that the adoptive transfer of allogeneic HSCs and allogeneic T lymphocytes can induce profound structural and spatial changes of bone tissue homeostasis as well as bone marrow cell composition, underlining the importance of the adaptive immune system for maintaining a balanced bone biology.
- Published
- 2020
- Full Text
- View/download PDF
19. Reduced Calcium Signaling Is Associated With Severe Graft-Versus-Host Disease: Results From Preclinical Models and From a Prospective EBMT Study.
- Author
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Riesner K, Cordes S, Peczynski C, Kalupa M, Schwarz C, Shi Y, Mertlitz S, Mengwasser J, van der Werf S, Peric Z, Koenecke C, Schoemans H, Duarte RF, Basak GW, and Penack O
- Subjects
- Animals, Biomarkers, Calcium blood, Disease Models, Animal, Female, Graft vs Host Disease diagnosis, Hematopoietic Stem Cell Transplantation adverse effects, Immunophenotyping, Incidence, Leukocytes immunology, Leukocytes metabolism, Mice, Knockout, Mice, Transgenic, Prognosis, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled metabolism, Recurrence, Transplantation, Homologous, Calcium Signaling, Disease Susceptibility, Graft vs Host Disease etiology, Graft vs Host Disease metabolism
- Abstract
Despite its involvement in various immune functions, including the allogeneic activation of T-lymphocytes, the relevance of calcium (Ca
2+ ) for GVHD pathobiology is largely unknown. To elucidate a potential association between Ca2+ and GVHD, we analyzed Ca2+ -sensing G-protein coupled receptor 6a (GPRC6a) signaling in preclinical GVHD models and conducted a prospective EBMT study on Ca2+ serum levels prior alloSCT including 363 matched sibling allogeneic peripheral blood stem cell transplantations (alloSCTs). In experimental models, we found decreased Gprc6a expression during intestinal GVHD. GPRC6a deficient alloSCT recipients had higher clinical and histopathological GVHD scores leading to increased mortality. As possible underlying mechanism, we found increased antigen presentation potential in GPRC6a-/- alloSCT recipients demonstrated by higher proliferation rates of T-lymphocytes. In patients with low Ca2+ serum levels (≤median 2.2 mmol/l) before alloSCT, we found a higher incidence of acute GVHD grades II-IV (HR = 2.3 Cl = 1.45-3.85 p = 0.0006), severe acute GVHD grades III-IV (HR = 3.3 CI = 1.59-7.14, p = 0.002) and extensive chronic GVHD (HR = 2.0 Cl = 1.04-3.85 p = 0.04). In conclusion, experimental and clinical data suggest an association of reduced Ca2+ signaling with increased severity of GVHD. Future areas of interest include the in depth analysis of involved molecular pathways and the investigation of Ca2+ signaling as a therapeutic target during GVHD., (Copyright © 2020 Riesner, Cordes, Peczynski, Kalupa, Schwarz, Shi, Mertlitz, Mengwasser, van der Werf, Peric, Koenecke, Schoemans, Duarte, Basak and Penack.)- Published
- 2020
- Full Text
- View/download PDF
20. Organ siderosis and hemophagocytosis during acute graft-versus-host disease.
- Author
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Nogai A, Shi Y, Pérez-Hernandez D, Cordes S, Mengwasser J, Mertlitz S, Riesner K, Kalupa M, Erdmann JH, Ziebig R, Dittmar G, and Penack O
- Subjects
- Acute Disease, Animals, Ferritins blood, Graft vs Host Disease immunology, Graft vs Host Disease mortality, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation mortality, Humans, Macrophage Activation, Mice, Retrospective Studies, Survival Analysis, Transplantation, Homologous, Cytophagocytosis, Graft vs Host Disease pathology, Hemosiderosis etiology
- Published
- 2016
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21. Hepatitis C coinfection enhances sensitization of CD4(+) T-cells towards Fas-induced apoptosis in viraemic and HAART-controlled HIV-1-positive patients.
- Author
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Körner C, Tolksdorf F, Riesner K, Krämer B, Schulte D, Nattermann J, Rockstroh JK, and Spengler U
- Subjects
- Adult, Aged, Antiretroviral Therapy, Highly Active, CD4-Positive T-Lymphocytes immunology, Coinfection, Female, HIV Infections immunology, HIV-1 immunology, Hepacivirus immunology, Hepatitis C immunology, Humans, Male, Middle Aged, fas Receptor blood, Apoptosis, CD4-Positive T-Lymphocytes physiology, Fas Ligand Protein metabolism, HIV Infections complications, HIV Infections drug therapy, Hepatitis C complications, fas Receptor metabolism
- Abstract
Background: Recently, we identified increased rates of CD4(+) T-cell apoptosis in HCV-infected HIV-positive patients as a potential mechanism for enhanced mortality in patients with HIV/HCV coinfection. Since this effect might be attributed to changes in receptor-induced apoptosis, we studied expression and function of Fas ligand (FasL) and its death receptor Fas on CD4(+) T-cells in HIV/HCV coinfection., Methods: In this cross-sectional study, we simultaneously analysed surface expression of Fas and FasL on CD4(+) T-cells and serum levels of soluble FasL in HCV/HIV-coinfected, HIV-monoinfected and HCV-monoinfected patients. Susceptibility to FasL-induced apoptosis was analysed by incubating isolated peripheral blood mononuclear cells with rhFasL followed by measuring CD4(+) T-cell apoptosis., Results: HIV and HCV monoinfection were associated with significantly enhanced surface expression of Fas. Highest Fas expression was detected in HIV/HCV-coinfected patients and correlated with low CD4(+) T-cell counts. By contrast, elevated levels of soluble and cellular FasL were found only in patients with HIV infection, but not in patients with HCV infection. Importantly, enhanced Fas expression in HCV/HIV coinfection rendered CD4(+) T-cells more susceptible towards FasL-induced apoptosis. While effective HAART normalized expression and secretion of FasL in HIV-infected and HIV/HCV-coinfected patients, expression of Fas decreased only slightly and still remained significantly elevated as compared with healthy controls., Conclusions: Our findings suggest a synergistic mechanism in HIV/HCV coinfection between up-regulation of Fas expression on CD4(+) T-cells and HIV-induced elevated levels of cellular and soluble FasL. Together, both effects contribute to enhanced apoptosis of CD4(+) T-cells in HIV/HCV coinfection.
- Published
- 2011
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