Marit Inngjerdingen

• Henden, Camilla; Fjerdingstad, Hege Brincker; Bjørnsen, Elisabeth Gyllensten; Thiruchelvam-Kyle, Lavanya; Daws, Michael Rory & Inngjerdingen, Marit [Vis alle 8 forfattere av denne artikkelen] (2025). NK-cell cytotoxicity toward pluripotent stem cells and their neural progeny: impacts of activating and inhibitory receptors and KIR/HLA mismatch. Stem Cells. ISSN 1066-5099. 43(3). doi: 10.1093/stmcls/sxae083. Fulltekst i vitenarkiv Vis sammendrag

  Pluripotent stem cells provide opportunities for treating injuries and previously incurable diseases. A major concern is the immunogenicity of stem cells and their progeny. Here, we have dissected the molecular mechanisms that allow natural killer (NK) cells to respond to human pluripotent stem cells, investigating a wide selection of activating and inhibitory NK-cell receptors and their ligands. Reporter cells expressing the activating receptor NKG2D responded strongly to embryonic stem (ES) cell lines and induced pluripotent stem (iPS) cell lines, whereas reporter cells expressing the activating receptors NKp30, NKp46, KIR2DS1, KIR2DS2, and KIR2DS4 did not respond. Human ES and iPS cells invariably expressed several ligands for NKG2D. Expression of HLA-C and HLA-E was lacking or low, insufficient to trigger reporter cells expressing the inhibitory receptors KIR2DL1, -2DL2, or -2DL3. Similar results were obtained for the pluripotent embryonic carcinoma cell lines NTERA-2 and 2102Ep, and also iPS-cell-derived neural progenitor cells. Importantly, neural progenitor cells and iPS-cell-derived motoneurons also expressed B7H6, the ligand for the activating receptor NKp30. In line with these observations, IL-2-stimulated NK cells showed robust cytotoxic responses to ES and iPS cells as well as to iPS-cell-derived motoneurons. No significant differences in cytotoxicity levels were observed between KIR/HLA matched and mismatched combinations of NK cells and pluripotent targets. Together, these data indicate that pluripotent stem cells and their neural progeny are targets for NK-cell killing both by failing to sufficiently express ligands for inhibitory receptors and by expression of ligands for activating receptors.

• Carrasco-Rojas, Javiera; Zavala, Gabriela; Contreras-Lopez, Rafael; Olivares, Belén; Larsen, Miriam Aarsund & Inngjerdingen, Marit [Vis alle 13 forfattere av denne artikkelen] (2025). Artificial cell-derived vesicles by extrusion, a novel docetaxel drug delivery system for lung cancer. Journal of Drug Delivery Science and Technology. ISSN 1773-2247. 106. doi: 10.1016/j.jddst.2025.106693. Fulltekst i vitenarkiv
• Mohamed, Warsan Nora; Butt, Hussain Shakeel; Schmidt, Thomas J.; Eltvik, Andrea Angelov; Wu, Desheng & Malterud, Karl Egil [Vis alle 9 forfattere av denne artikkelen] (2025). Biflavonoids and bi- and tricoumarins from Daphne mezereum and inhibition of TNF-α secretion. Phytochemistry. ISSN 0031-9422. 229. doi: 10.1016/j.phytochem.2024.114308. Fulltekst i vitenarkiv Vis sammendrag

  Daphne mezereum L. (Thymelaeaceae) was an important medicinal plant in Norway during the 18th and 19th centuries and used against diseases such as diarrhea, swelling, stomach pain, and tuberculosis. Five previously undescribed phenolic compounds, including two biflavonoids with a catechin core structure, two tricoumarins, and one bicoumarin, together with ten known compounds were isolated from a 50% EtOH extract of the bark of D. mezereum. Using NMR, HRESIMS, acid hydrolysis, and circular dichroism spectra, the biflavonoids were identified as 3′-hydroxygenkwanol A and 3′-hydroxydihydrodaphnodorin B, and the coumarins were identified as 3‴-O-acetyltriumbellin, triumbellin 4‴-O-β-d-glucopyranoside, and daphnogitin-7-O-β-d-glucopyranoside. The absolute configuration of dihydrodaphnodorin B was for the first time established as 2R, 3S, 2″S, 3″S. Daphnin, syringin, 3′-hydroxydihydrodaphnodorin B, dihydrodaphnodorin B, and neochamaejasmin A and B were identified as the major secondary metabolites in the extract. Neochamaejasmin A and B showed the most potent inhibition of TNF-α secretion in Con A stimulated peripheral blood mononuclear cells (PBMCs) with 71.3 ± 3.4 and 83.5 ± 11.5% inhibition, respectively, at 50 μM.

• Wu, Yunjie; Chollet, Héloïse; Sudworth, Amanda & Inngjerdingen, Marit (2025). Evaluating the Influence of Different Serum-Free Culture Conditions on the Production and Function of Natural Killer Cell-Derived Extracellular Vesicles. Journal of Extracellular Biology (J Ex Bio). 4(4). doi: 10.1002/jex2.70049. Fulltekst i vitenarkiv Vis sammendrag

  Natural killer (NK) cells are exploited in cellular therapies for cancer. While NK cell therapies are efficient against haematological cancers, it has been difficult to target solid tumours due to low tumour infiltration and a hostile tumour microenvironment. NK-cell derived extracellular vesicles (NK-EVs) target and kill cancer cells in vitro and represent an alternative treatment strategy for solid tumours. To exploit their potential, it is necessary to standardize NK-EV production protocols. Here, we have performed a comparative analysis of EVs from the human NK-92 cell line cultured in five serum-free commercial media optimized for growth of human NK cells and one serum-free medium for growth of lymphocytes. The effect of growing the NK-92 cells in static cell cultures versus shaking flasks was compared. EVs were purified via ultracentrifugation followed by size-exclusion chromatography. We found that there were no significant differences in EV yield from NK-92 cells grown under static or dynamic conditions. However, we found clear differences between the different culture media in terms of EV purity as assessed by the enrichment of the CD63 and CD81 markers in the isolates that translated into their capacity to induce apoptosis of the colon cancer cell line HCT 116. These findings will be instructive for the design of future production protocols for therapeutic NK-cell derived EVs.

• Eltvik, Andrea Angelov; Inngjerdingen, Marit & Wangensteen, Helle (2025). In vitro anti-inflammatory properties of twelve Norwegian medicinal plants. Journal of Ethnopharmacology. ISSN 0378-8741. 352. doi: 10.1016/j.jep.2025.120159. Fulltekst i vitenarkiv Vis sammendrag

  Ethnopharmacological relevance Today, inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease represent a major health burden in Western societies. Such diseases are treated with drugs aiming at suppressing inflammatory symptoms. In Norway, several medicinal plants share a history of ethnomedical use towards the treatment of various inflammatory conditions which could represent sources of new anti-inflammatory drugs. Aim of the study This study focused on exploring the potential of understudied traditional medicinal plants used in Norway to treat inflammation of different origin. Through phytochemical and biological screening methods, we aimed to identify plants with anti-inflammatory properties that also showed a high proportion of phenolic compounds. Based on these results, such plants would be of interest and relevance for further work including isolation and characterization of phytochemicals that could serve as novel anti-inflammatory drugs. Materials and methods A systematic literature survey of historical records from the 1800s and onwards was performed searching for plants used to treat various inflammatory diseases. Twelve plants were selected and subjected to accelerated solvent extraction to obtain extracts rich in phenolic compounds, namely dichloromethane and 80 % ethanol extracts. These were studied in bioassays assessing their in vitro anti-inflammatory effects. Their ability to inhibit nitric oxide (NO) and TNF-α cytokine production was measured, and their protection against indomethacin induced damage of the intestinal epithelial barrier was evaluated using differentiated Caco-2 cells. The total phenolic content of the extracts was determined, and 1H NMR spectroscopy and HPLC-DAD was performed for phytochemical profiling. Results Several of the plants presented moderate to high bioactivity, namely Matricaria discoidea, Alnus incana, Geranium sylvaticum, Antennaria dioica, Tanacetum vulgare and Malva moschata. A stronger effect was observed among the dichloromethane extracts in NO and TNF-α inhibition, while the 80 % ethanol extracts showed greater protection of the barrier integrity. M. discoidea, A. incana and G. sylvaticum are of particular interest, presenting consistently high bioactivity. Their 1H NMR spectra also showed a high proportion of phenolic compounds. Conclusion Both A. incana and M. discoidea are scarcely studied regarding their bioactivity and chemical composition, being potential candidates for the discovery of novel anti-inflammatory drugs. Based on the results obtained from this study, further work will focus on these two plants, including isolation of phenolic compounds and assessing their biological activities.

• Butt, Hussain Shakeel; Ulriksen, Emilie Steinbakk; Rise, Frode; Wangensteen, Helle; Duus, Jens Øllgaard & Inngjerdingen, Marit [Vis alle 7 forfattere av denne artikkelen] (2024). Structural elucidation of novel pro-inflammatory polysaccharides from Daphne mezereum L. Carbohydrate Polymers. ISSN 0144-8617. 324:121554, s. 1–15. doi: 10.1016/j.carbpol.2023.121554. Fulltekst i vitenarkiv Vis sammendrag

  Daphne mezereum L., an important medicinal plant in Scandinavian folk medicine, was used to treat ailments such as diarrhea, swelling and stomach pain. A range of natural compounds have been isolated, but little attention has been given to the polysaccharides in this plant. Previous work in our group have shown that a polysaccharide enriched fraction from the bark of D. mezereum exhibited pro-inflammatory effects. To pursue this further, the aim of the present work was to isolate and characterize these polysaccharides. From the ethanol-precipitate of a water extract, one neutral (DMP-NF) and one acidic (DMP-AF) fraction was isolated by anion-exchange chromatography. GC, GC–MS and 1D- and 2D-NMR were used to characterize the polysaccharide structures. DMP-NF appeared to be a mixture of arabinan, arabinogalactan and hemicelluloses such as xyloglucan, mannan and xylan. DMP-AF contained a pectic polysaccharide mainly consisting of an unusually long homogalacturonan backbone. Enzymatic treatment by pectinase of DMP-AF yielded DMP-ED, which contained a rhamnogalacturonan-I backbone with arabinan, galactan and arabinogalactan side chains. Both DMP-NF and DMP-ED induced IFN-γ and TNF-α secretion in peripheral blood mononuclear cells (PBMCs), DMP-ED being the most potent fraction. DMP-AF was less active, which might be due to a less sterically available rhamnogalacturonan-I domain.

• Atzler, Michael; Baudrexler, Tobias; Amberger, Daniel Christoph; Rogers, Nicole; Rabe, Alexander & Schmohl, Joerg [Vis alle 15 forfattere av denne artikkelen] (2024). In Vivo Induction of Leukemia-Specific Adaptive and Innate Immune Cells by Treatment of AML-Diseased Rats and Therapy-Refractory AML Patients with Blast Modulating Response Modifiers. International Journal of Molecular Sciences. ISSN 1661-6596. 25:13469(24), s. 1–17. doi: 10.3390/ijms252413469. Fulltekst i vitenarkiv Vis sammendrag

  There is a high medical need to develop new strategies for the treatment of patients with acute myeloid leukemia (AML) refractory to conventional therapy. In vitro, the combinations of the blast-modulatory response modifiers GM-CSF + Prostaglandin E1, (summarized as Kit M) have been shown to convert myeloid leukemic blasts into antigen-presenting dendritic cells of leukemic origin (DCleu) that were able to (re-)activate the innate and adaptive immune system, direct it specifically against leukemic blasts, and induce memory cells. This study aimed to investigate the immune modulatory capacity and antileukemic efficacy of Kit M in vivo. Brown Norway rats suffering from AML were treated with Kit M (twofold application). Blasts and immune cells were monitored in peripheral blood (PB) and spleen. Upon the observation of promising immune modulatory effects in the treated animals, two patients with AML refractory to multiple lines of therapy were offered treatment with Kit M on an individualized basis. Safety, as well as immunological and clinical effects, were monitored. Samples obtained from a third patient in similar clinical conditions not receiving Kit M were used as controls for immune monitoring tests. Animal experiments: Drugs were well tolerated by the treated animals. After 9 days of treatment, DCleu and memory-like T cells increased in the peripheral blood, whereas regulatory T cells, especially blasts, decreased in treated as compared to untreated control animals. Clinical courses: No severe side effects were observed. In patient 1482, PB blasts remained under the detection threshold during 27 days of treatment, thrombocytes were normalized, and (leukemia specific) immune effector cells of the adaptive and innate immune system increased up to 800-fold compared to the start of treatment. Patient 1601 responded with a 12% reduction in blasts in PB immediately after Kit M treatment. Several subtypes of (leukemia-specific) immune effector cells in PB increased up to four-fold during the 19 days of treatment. In contrast, immune-reactive cells decreased under mild chemotherapy in the PB of control patient 1511 with comparably refractory AML. Within the limitation of low numbers in both animal experiments and clinical applications, our data suggest that Kit M treatment of AML-diseased rats and patients is feasible and may induce leukemia-specific immune reactions and clinical improvement. A larger series and a prospective clinical trial will be required to confirm our observations. Beyond optimized doses and schedules of the applied compounds, the combination with other antileukemic strategies or the application of Kit M in less proliferative stages of the myeloid diseases need to be discussed. If effects are confirmed, the concept may add to the armamentarium of treatments for highly aggressive blood cancer.

• Welsh, Joshua A.; Andaloussi, Samir E. L.; Arntz, Onno J.; Arsène, Pierre; Arteaga-Blanco, Luis & Aspelin, Trude [Vis alle 898 forfattere av denne artikkelen] (2024). Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches. Journal of Extracellular Vesicles. 13:e12404(2), s. 1–84. doi: 10.1002/jev2.12404. Fulltekst i vitenarkiv Vis sammendrag

  Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its ‘Minimal Information for Studies of Extracellular Vesicles’, which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly.

• Langer, Ronja; Lelas, Antonela; Rittenschober, Michael; Piekarska, Agnieszka; Sadowska-Klasa, Alicja & Sabol, Ivan [Vis alle 20 forfattere av denne artikkelen] (2024). Retrospective analysis of the incidence and outcome of late acute and chronic graft-versus-host disease—an analysis from transplant centers across Europe. Frontiers in Transplantation. 3:1332181, s. 1–13. doi: 10.3389/frtra.2024.1332181. Fulltekst i vitenarkiv Vis sammendrag

  Introduction: Chronic graft-versus-host disease (cGvHD) is a serious late complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: This multicenter analysis determined the cumulative incidence (CI) of cGvHD and late acute GvHD (laGvHD) and its impact on transplantation-related mortality (TRM), relapse (R), and overall survival (OS) in 317 patients [296 adults, 21 pediatrics (<12 years of age)] who underwent their first allo-HSCT in 2017. Results: The CI of laGvHD was 10.5% in adults and 4.8% in pediatrics, and the CI of cGvHD was 43.0% in all adult transplant patients and 50.2% in the adult at-risk cohort at the study end. The onset of cGvHD was de novo in 42.0% of patients, quiescent in 52.1%, and progressive in 5.9%. In adults, prophylactic use of antithymocyte globulin or posttransplant cyclophosphamide was associated with a significantly lower incidence of cGvHD (28.7%) vs. standard prophylaxis with calcineurin inhibitors (30.6%) and methotrexate/mycophenolate mofetil (58.4%) (all p < 0.01). TRM was significantly higher in patients with aGvHD (31.8%) vs. cGvHD (12.6%) and no GvHD (6.3%) (all p = 0.0001). OS in the adult at-risk cohort was significantly higher in patients with cGvHD (78.9%) vs. without (66.2%; p = 0.0022; HR 0.48) due to a significantly lower relapse rate (cGvHD: 14.5%; without cGvHD: 27.2%; p = 0.00016, HR 0.41). OS was also significantly higher in patients with mild (80.0%) and moderate (79.2%) cGvHD vs. without cGvHD (66.2%), excluding severe cGvHD (72.7%) (all p = 0.0214). Discussion: The negative impact of severe cGvHD on OS suggests a focus on prevention of severe forms is warranted to improve survival and quality of life.

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• Gjærde, Lars Klingen; Brück, Oscar; Gagelmann, Nico; Gavriilaki, Eleni; Inngjerdingen, Marit & Keranen, Mikko [Vis alle 24 forfattere av denne artikkelen] (2024). Standardized translations of the Lee Chronic GvHD Symptom Scale to 12 European languages: an EU COST Action cGvHD Eurograft project. Bone Marrow Transplantation. ISSN 0268-3369. doi: 10.1038/s41409-024-02374-4. Fulltekst i vitenarkiv

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