TY - JOUR AU - Bakos, Tamás AU - Mészáros, Tamás AU - Kozma, Gergely Tibor AU - Berényi, Petra AU - Facskó, Réka AU - Farkas, Henriette AU - Dézsi, László AU - Heirman, Carlo AU - de Koker, Stefaan AU - Schiffelers, Raymond AU - Glatter, Kathryn Anne AU - Radovits, Tamás AU - Szénási, Gábor AU - Szebeni, János TI - mRNA-LNP COVID-19 Vaccine Lipids Induce Complement Activation and Production of Proinflammatory Cytokines: Mechanisms, Effects of Complement Inhibitors, and Relevance to Adverse Reactions JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 25 PY - 2024 IS - 7 PG - 17 SN - 1661-6596 DO - 10.3390/ijms25073595 UR - https://m2.mtmt.hu/api/publication/34754128 ID - 34754128 AB - A small fraction of people vaccinated with mRNA–lipid nanoparticle (mRNA-LNP)-based COVID-19 vaccines display acute or subacute inflammatory symptoms whose mechanism has not been clarified to date. To better understand the molecular mechanism of these adverse events (AEs), here, we analyzed in vitro the vaccine-induced induction and interrelations of the following two major inflammatory processes: complement (C) activation and release of proinflammatory cytokines. Incubation of Pfizer-BioNTech’s Comirnaty and Moderna’s Spikevax with 75% human serum led to significant increases in C5a, sC5b-9, and Bb but not C4d, indicating C activation mainly via the alternative pathway. Control PEGylated liposomes (Doxebo) also induced C activation, but, on a weight basis, it was ~5 times less effective than that of Comirnaty. Viral or synthetic naked mRNAs had no C-activating effects. In peripheral blood mononuclear cell (PBMC) cultures supplemented with 20% autologous serum, besides C activation, Comirnaty induced the secretion of proinflammatory cytokines in the following order: IL-1α < IFN-γ < IL-1β < TNF-α < IL-6 < IL-8. Heat-inactivation of C in serum prevented a rise in IL-1α, IL-1β, and TNF-α, suggesting C-dependence of these cytokines’ induction, although the C5 blocker Soliris and C1 inhibitor Berinert, which effectively inhibited C activation in both systems, did not suppress the release of any cytokines. These findings suggest that the inflammatory AEs of mRNA-LNP vaccines are due, at least in part, to stimulation of both arms of the innate immune system, whereupon C activation may be causally involved in the induction of some, but not all, inflammatory cytokines. Thus, the pharmacological attenuation of inflammatory AEs may not be achieved via monotherapy with the tested C inhibitors; efficacy may require combination therapy with different C inhibitors and/or other anti-inflammatory agents. LA - English DB - MTMT ER - TY - JOUR AU - Pethő, Ákos AU - Schnabel, Karolina Kornélia AU - Dézsi, László TI - Complement-mediated dialysis reaction during regular hemodialysis treatment: a case report JF - JOURNAL OF MEDICAL CASE REPORTS J2 - J MED CASE REP VL - 18 PY - 2024 IS - 1 PG - 4 SN - 1752-1947 DO - 10.1186/s13256-024-04365-x UR - https://m2.mtmt.hu/api/publication/34571861 ID - 34571861 N1 - Export Date: 20 April 2024 Correspondence Address: Pethő, Á.; Department of Internal Medicine and Oncology, Korányi S. U. 2/a, Hungary; email: petho.akos@med.semmelweis-univ.hu Chemicals/CAS: allopurinol, 315-30-0, 17795-21-0; bicarbonate, 144-55-8, 71-52-3; calcium, 7440-70-2, 14092-94-5; carvedilol, 72956-09-3; cinacalcet, 226256-56-0, 364782-34-3; colecalciferol, 1406-16-2, 67-97-0; glucose, 50-99-7, 84778-64-3, 8027-56-3; heparin, 37187-54-5, 8057-48-5, 8065-01-8, 9005-48-5, 9041-08-1; magnesium, 7439-95-4; mycophenolate mofetil, 116680-01-4, 128794-94-5, 115007-34-6; pantoprazole, 102625-70-7, 164579-32-2, 138786-67-1; potassium, 7440-09-7; prednisolone, 50-24-8; sevelamer, 182683-00-7, 152751-57-0, 198342-66-4, 198343-01-0, 224313-14-8, 52757-95-6; sodium, 7440-23-5; tacrolimus, 104987-11-3, 109581-93-3 Manufacturers: Fresenius Medical Care, Germany LA - English DB - MTMT ER - TY - GEN AU - Bakos, Tamás AU - Mészáros, Tamás AU - Kozma, Gergely Tibor AU - Petra, Berényi AU - Facskó, Réka AU - Henriette, Farkas AU - Dézsi, László AU - Carlo, Heirman AU - Stefaan, de Koker AU - Raymond, Schiffelers AU - Kathryn, Anne Glatter AU - Radovits, Tamás AU - Szénási, Gábor AU - Szebeni, János TI - mRNA-LNP COVID-19 vaccine lipids induce low level complement activation and production of proinflammatory cytokines: Mechanisms, effects of complement inhibitors, and relevance to adverse reactions PY - 2024 SP - & UR - https://m2.mtmt.hu/api/publication/34521339 ID - 34521339 AB - Messenger RNA-containing lipid nanoparticles (mRNA-LNPs) enabled widespread COVID-19 vaccination with a small fraction of vaccine recipients displaying acute or sub-acute inflammatory symptoms. The molecular mechanism of these adverse events (AEs) remains undetermined. Here we report that the mRNA-LNP vaccine, Comirnaty, triggers low-level complement (C) activation and production of inflammatory cytokines, which may be key underlying processes of inflammatory AEs. In serum, Comirnaty and the control PEGylated liposome (Doxebo) caused different rises of C split products, C5a, sC5b-9, Bb and C4d, indicating stimulation of the classical pathway of C activation mainly by the liposomes, while a stronger stimulation of the alternative pathway was equal with the vaccine and the liposomes. Spikevax had similar C activation as Comirnaty, but viral or synthetic mRNAs had no such effect. In autologous serum-supplemented peripheral blood mononuclear cell (PBMC) cultures, Comirnaty caused increases in the levels of sC5b-9 and proinflammatory cytokines in the following order: IL-1α < IFN-γ < IL-1β < TNF-α < IL-6 < IL-8, whereas heatinactivation of serum prevented the rises of IL-1α, IL-1β, and TNF-α. Clinical C inhibitors, Soliris and Berinert, suppressed vaccine-induced C activation in serum but did not affect cytokine production when applied individually. These findings suggest that the PEGylated lipid coating of mRNA-LNP nanoparticles can trigger C activation mainly via the alternative pathway, which may be causally related to the induction of some, but not all inflammatory cytokines. While innate immune stimulation is essential for the vaccine’s efficacy, concurrent production of C- and PBMC-derived inflammatory mediators may contribute to some of the AEs. Pharmacological attenuation of harmful cytokine production using C inhibitors likely requires blocking the C cascade at multiple points. LA - English DB - MTMT ER - TY - GEN AU - Szénási, Gábor AU - Bakos, Tamás AU - Őrfi, Erik AU - Mészáros, Tamás AU - Hricisák, László AU - Rosivall, László AU - Hamar, Péter AU - Benyó, Zoltán AU - Szebeni, János AU - Dézsi, László TI - COMPARISON OF LIPOSOMAL DRUG-INDUCED BLOOD PRESSURE CHANGES IN MICE AND RATS PY - 2023 SP - 73 EP - 73 PG - 1 UR - https://m2.mtmt.hu/api/publication/34747635 ID - 34747635 AB - Introduction: Liposomal drugs administered intravenously (i.v.) can induce IgEindependent side effects known as infusion reaction, and also termed as complement activation-related pseudoallergy (CARPA). Aim: We aimed to reveal the basic mechanisms of blood pressure changes after i.v. injection of amphotericin B-containing liposomes (Abelcet, rats: 10 mg/kg; mice: 30 mg/kg). Methods: Male NMRI mice, and wild type or thromboxane prostanoid receptor deficient (TP KO) mice on C57Bl/6 background, as well as male Wistar rats (anesthetized with pentobarbital) were used (n=6-8/group). Mean arterial blood pressure was continuously monitored. Blood was collected at 0, 1, 3 10 and 30 min in rats, and from separate groups of mice at 3-5 min after treatment. Plasma C3a and thromboxane B2 (TXB2) concentrations were assayed using ELISA. Blood count was obtained using a hematology analyzer (Abacus Vet5). Results: Abelcet caused transient hypertension in mice (10-15 min) and transient hypotension in rats (20-40 min). Abelcet resulted in leucopenia and thrombocytopenia, and increased plasma complement C3a and TXB2 concentrations in both species. Complement depletion with cobra venom factor (CVF) lengthened the hypertensive effect in mice and abolished the hypotensive effect in rats. Pretreatment with DF2593A (10 mg/kg, i.v.), a C5a receptor (C5aR) antagonist, lengthened the hypertensive effect of Abelcet in mice and elicited a small decrease in the hypotensive effect in rats. Inhibition of C3a receptors with SB290157 (10 mg/kg) attenuated the hypertension in mice and enhanced the hypotension in rats, but both effects were rather small. Macrophage depletion with clodronate liposomes in mice lengthened the hypertensive effect similarly to CVF. Pre-treatment with GdCl3 to inhibit macrophages slightly attenuated the hypotensive effect of Abelcet in rats. Inhibition of mast cell activation by cromolyn or C48/80, decreased the hypotensive response in rats, but induced delayed hypotension in mice, respectively. Inhibition of platelet activation using eptifibatide, a platelet glycoprotein IIb/IIIa (GPIIb/IIIa) receptor inhibitor, lengthened the hypertensive effect in mice, but hardly affected the responses in rats. Abelcet did not change blood pressure in TP KO mice and led to a delayed hypertension after pretreatment with CVF. Conclusion: Our results suggest that complement activation has a small contribution to liposomal drug-induced hypotension, and both macrophages and mast cells contribute to the release of vasoactive mediators in rats. The early hypertensive effect of TXA2 release in mice wasindependent from complement activation, and wasreversed with some delay mainly by the activation of C5aR. Both macrophages and platelets are substantially implicated in the latter effect. LA - English DB - MTMT ER - TY - JOUR AU - Unterweger, Harald AU - Janko, Christina AU - Folk, Tamara AU - Cicha, Iwona AU - Stelczerné Kovács, Noémi AU - Gyebnár, Gyula AU - Horváth, Ildikó AU - Máthé, Domokos AU - Zheng, Kang H. AU - Coolen, Bram F. AU - Stroes, Erik AU - Szebeni, János AU - Alexiou, Christoph AU - Dézsi, László AU - Lyer, Stefan TI - Comparative in vitro and in vivo Evaluation of Different Iron Oxide-Based Contrast Agents to Promote Clinical Translation in Compliance with Patient Safety JF - INTERNATIONAL JOURNAL OF NANOMEDICINE J2 - INT J NANOMED VL - 18 PY - 2023 SP - 2071 EP - 2086 PG - 16 SN - 1176-9114 DO - 10.2147/IJN.S402320 UR - https://m2.mtmt.hu/api/publication/33856424 ID - 33856424 N1 - ENT-Department, Section of Experimental Oncology und Nanomedicine (SEON), Universitätsklinikum Erlangen, Erlangen, Germany Hungarian Centre of Excellence for Molecular Medicine, Semmelweis University, Budapest, Hungary Medical Imaging Centre, Semmelweis University, Budapest, Hungary Department Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam, Netherlands Department of Biomedical Engineering and Physics, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam, Netherlands Nanomedicine Research and Education Center, Institute of Translational Medicine, Semmelweis University, Budapest, Hungary SeroScience Ltd, Budapest, Hungary Export Date: 1 June 2023 Correspondence Address: Unterweger, H.; Universitätsklinikum Erlangen, Glueckstr. 10a, Germany; email: harald.unterweger@uk-erlangen.de AB - Introduction: One of the major challenges in the clinical translation of nanoparticles is the development of formulations combining favorable efficacy and optimal safety. In the past, iron oxide nanoparticles have been introduced as an alternative for gadolinium-containing contrast agents; however, candidates available at the time were not free from adverse effects.Methods: Following the development of a potent iron oxide-based contrast agent SPIONDex, we now performed a systematic comparison of this formulation with the conventional contrast agent ferucarbotran and with ferumoxytol, taking into consideration their physicochemical characteristics, bio-and hemocompatibility in vitro and in vivo, as well as their liver imaging properties in rats.Results: The results demonstrated superior in vitro cyto-, hemo-and immunocompatibility of SPIONDex in comparison to the other two formulations. Intravenous administration of ferucarbotran or ferumoxytol induced strong complement activation-related pseu-doallergy in pigs. In contrast, SPIONDex did not elicit any hypersensitivity reactions in the experimental animals. In a rat model, comparable liver imaging properties, but a faster clearance was demonstrated for SPIONDex.Conclusion: The results indicate that SPIONDex possess an exceptional safety compared to the other two formulations, making them a promising candidate for further clinical translation. LA - English DB - MTMT ER - TY - JOUR AU - Őrfi, Erik AU - Hricisák, László AU - Dézsi, László AU - Hamar, Péter AU - Benyó, Zoltán AU - Szebeni, János AU - Szénási, Gábor TI - The Hypertensive Effect of Amphotericin B-Containing Liposomes (Abelcet) in Mice: Dissecting the Roles of C3a and C5a Anaphylatoxins, Macrophages and Thromboxane JF - BIOMEDICINES J2 - BIOMEDICINES VL - 10 PY - 2022 IS - 7 PG - 12 SN - 2227-9059 DO - 10.3390/biomedicines10071764 UR - https://m2.mtmt.hu/api/publication/33022184 ID - 33022184 N1 - Funding Agency and Grant Number: Semmelweis University; European Union [825828, 952520]; National Research, Development, and Innovation Office (NKFIH) of Hungary [2020-1.1.6-JOVO-2021-00013]; Applied Materials and Nanotechnology Center of Excellence, Miskolc University, Miskolc, Hungary; New National Excellence Program of the Ministry for Innovation and Technology, NKFIH [UNKP-19-3-III, OTKA K-101775, K-115623, K-113164, K-125174] Funding text: Open access funding was provided by Semmelweis University. The financial support by the European Union Horizon 2020 projects 825828 "Expert" and 952520 "Biosafety" are acknowledged. This project was also supported by a grant from the National Research, Development, and Innovation Office (NKFIH) of Hungary (2020-1.1.6-JOVO-2021-00013). JS thanks the support by the Applied Materials and Nanotechnology Center of Excellence, Miskolc University, Miskolc, Hungary. E.O. was supported by the UNKP-19-3-III New National Excellence Program of the Ministry for Innovation and Technology, NKFIH OTKA K-101775, K-115623, K-113164, and K-125174 grants. LA - English DB - MTMT ER - TY - JOUR AU - Dézsi, László AU - Mészáros, Tamás AU - Kozma, Gergely Tibor AU - H-Velkei, Mária AU - Oláh, Csaba Zsolt AU - Szabó, Miklós AU - Patkó, Zsófia Panna AU - Fülöp, Tamás AU - Hennies, Mark AU - Szebeni, Miklós AU - Barta, Bálint András AU - Merkely, Béla Péter AU - Radovits, Tamás AU - Szebeni, János TI - A naturally hypersensitive porcine model may help understand the mechanism of COVID-19 mRNA vaccine-induced rare (pseudo) allergic reactions: complement activation as a possible contributing factor JF - GEROSCIENCE: OFFICIAL JOURNAL OF THE AMERICAN AGING ASSOCIATION (AGE) J2 - GEROSCIENCE VL - 44 PY - 2022 IS - 2 SP - 597 EP - 618 PG - 22 SN - 2509-2715 DO - 10.1007/s11357-021-00495-y UR - https://m2.mtmt.hu/api/publication/32666145 ID - 32666145 N1 - Tamás Radovits and János Szebeni contributed equally to the article. AB - A tiny fraction of people immunized with lipid nanoparticle (LNP)-enclosed mRNA (LNP-mRNA) vaccines develop allergic symptoms following their first or subsequent vaccinations, including anaphylaxis. These reactions resemble complement (C) activation-related pseudoallergy (CARPA) to i.v. administered liposomes, for which pigs provide a naturally oversensitive model. Using this model, we injected i.v. the human vaccination dose (HVD) of BNT162b2 (Comirnaty, CMT) or its 2-fold (2x) or 5-fold (5x) amounts and measured the hemodynamic changes and other parameters of CARPA. We observed in 6 of 14 pigs transient pulmonary hypertension along with thromboxane A2 release into the blood and other hemodynamic and blood cell changes, including hypertension, granulocytosis, lymphopenia, and thrombocytopenia. One pig injected with 5x CMT developed an anaphylactic shock requiring resuscitation, while a repeat dose failed to induce the reaction, implying tachyphylaxis. These typical CARPA symptoms could not be linked to animal age, sex, prior immune stimulation with zymosan, immunization of animals with Comirnaty i.v., or i.m. 2 weeks before the vaccine challenge, and anti-PEG IgM levels in Comirnaty-immunized pigs. Nevertheless, IgM binding to the whole vaccine, used as antigen in an ELISA, was significantly higher in reactive animals compared to non-reactive ones. Incubation of Comirnaty with pig serum in vitro showed significant elevations of C3a anaphylatoxin and sC5b-9, the C-terminal complex. These data raise the possibility that C activation plays a causal or contributing role in the rare HSRs to Comirnaty and other vaccines with similar side effects. Further studies are needed to uncover the factors controlling these vaccine reactions in pigs and to understand their translational value to humans. LA - English DB - MTMT ER - TY - JOUR AU - Pethő, Ákos AU - Piecha, Dorothea AU - Mészáros, Tamás AU - Urbanics, Rudolf AU - Moore, Christoph AU - Canaud, Bernard AU - Rosivall, László AU - Mollnes, Tom Eirik AU - Steppan, Sonja AU - Szénási, Gábor AU - Szebeni, János AU - Dézsi, László TI - A porcine model of hemodialyzer reactions: roles of complement activation and rinsing back of extracorporeal blood JF - RENAL FAILURE J2 - RENAL FAILURE VL - 43 PY - 2021 IS - 1 SP - 1609 EP - 1620 PG - 12 SN - 0886-022X DO - 10.1080/0886022X.2021.2007127 UR - https://m2.mtmt.hu/api/publication/32532068 ID - 32532068 N1 - Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary Fresenius Medical Care Deutschland GmbH, Bad Homburg, Germany SeroScience Ltd, Budapest, Hungary School of Medicine, Montpellier University, Montpellier, France International Nephrology Research and Training Center, Institute of Translational Medicine, Semmelweis University, Budapest, Hungary Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway Research Laboratory, Nordland Hospital Bodø and Faculty of Health Sciences and TREC, University of Tromsø, Tromsø, Norway Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway Nanomedicine Research and Education Center, Institute of Translational Medicine, Semmelweis University, Budapest, Hungary Export Date: 21 December 2021 CODEN: REFAE Correspondence Address: Szebeni, J.; Nanomedicine Research and Education Center, 1089 Nagyvarad t. 4, Hungary; email: jszebeni2@gmail.com LA - English DB - MTMT ER - TY - JOUR AU - Bakos, Tamás AU - Őrfi, Erik AU - Mészáros, Tamás AU - Milosevits, Gergely AU - Csukás, Domokos AU - Rosivall, László AU - Hamar, Péter AU - Dézsi, László AU - Szebeni, János AU - Szénási, Gábor TI - Complement Activation-Related Pseudoallergy (CARPA) in Rats; The Example of Liposomal Amphotericin-B (AmBisome) JF - ACTA PHARMACEUTICA HUNGARICA J2 - ACTA PHARM HUNG VL - 91 PY - 2021 IS - 3-4 SP - 175 EP - 176 PG - 2 SN - 0001-6659 UR - https://m2.mtmt.hu/api/publication/32509180 ID - 32509180 LA - English DB - MTMT ER - TY - JOUR AU - Milosevits, Gergely AU - Mészáros, Tamás AU - Őrfi, Erik AU - Bakos, Tamás AU - Garami, Miklós AU - Kovács, Gábor AU - Dézsi, László AU - Hamar, Péter AU - Győrffy, Balázs AU - Szabó, András AU - Szénási, Gábor AU - Szebeni, János TI - Complement-mediated hypersensitivity reactions to an amphotericin B-containing lipid complex (Abelcet) in pediatric patients and anesthetized rats: Benefits of slow infusion JF - NANOMEDICINE: NANOTECHNOLOGY BIOLOGY AND MEDICINE J2 - NANOMED: NANOTECHNOL VL - 34 PY - 2021 PG - 7 SN - 1549-9634 DO - 10.1016/j.nano.2021.102366 UR - https://m2.mtmt.hu/api/publication/31864261 ID - 31864261 N1 - * Megosztott szerzőség LA - English DB - MTMT ER -