TY - THES AU - Fülöp, Tamás TI - Hypersensitivity to polymer-coated nanomedicines : mechanism, prediction and prevention PY - 2023 SN - 9789036554633 DO - 10.3990/1.9789036554633 UR - https://m2.mtmt.hu/api/publication/33606840 ID - 33606840 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 - Vigne, Jonathan AU - Cabella, Claudia AU - Dézsi, László AU - Rustique, Emilie AU - Couffin, Anne-Claude AU - Aid, Rachida AU - Anizan, Nadège AU - Chauvierre, Cédric AU - Letourneur, Didier AU - Le Guludec, Dominique AU - Rouzet, François AU - Hyafil, Fabien AU - Mészáros, Tamás AU - Fülöp, Tamás AU - Szebeni, János AU - Cordaro, Alessia AU - Oliva, Paolo AU - Mourier, Véronique AU - Texier, Isabelle TI - Nanostructured lipid carriers accumulate in atherosclerotic plaques of ApoE−/− mice JF - NANOMEDICINE: NANOTECHNOLOGY BIOLOGY AND MEDICINE J2 - NANOMED: NANOTECHNOL VL - 25 PY - 2020 PG - 12 SN - 1549-9634 DO - 10.1016/j.nano.2020.102157 UR - https://m2.mtmt.hu/api/publication/31160845 ID - 31160845 N1 - Université de Paris, LVTS, INSERM U1148, Paris, France Nuclear Medicine Department, X. Bichat Hospital, APHP and DHU FIRE, Paris, France Université de Paris, UMS34 FRIM, Paris, France Centro Ricerche Bracco, Bracco Imaging SpA, Colleretto Giacosa, Italy Nanomedicine Research and Education Center, Institute of Pathophysiology, Semmelweis University, Budapest, Hungary University Grenoble Alpes, CEA, LETI, Grenoble, France Cited By :1 Export Date: 12 February 2021 Correspondence Address: Texier, I.; University Grenoble Alpes, France; email: Isabelle.texier-nogues@cea.fr LA - English DB - MTMT ER - TY - JOUR AU - Chauvierre, Cédric AU - Aid-Launais, Rachida AU - Aerts, Joël AU - Chaubet, Frédéric AU - Maire, Murielle AU - Chollet, Lucas AU - Rolland, Lydia AU - Bonafé, Roberta AU - Rossi, Silvia AU - Bussi, Simona AU - Cabella, Claudia AU - Dézsi, László AU - Fülöp, Tamás AU - Szebeni, János AU - Chahid, Youssef AU - Zheng, Kang H. AU - Stroes, Erik S. G. AU - Le Guludec, Dominique AU - Rouzet, François AU - Letourneur, Didier TI - Pharmaceutical Development and Safety Evaluation of a GMP-Grade Fucoidan for Molecular Diagnosis of Cardiovascular Diseases JF - MARINE DRUGS J2 - MAR DRUGS VL - 17 PY - 2019 IS - 12 PG - 17 SN - 1660-3397 DO - 10.3390/md17120699 UR - https://m2.mtmt.hu/api/publication/31118542 ID - 31118542 LA - English DB - MTMT ER - TY - JOUR AU - Dézsi, László AU - Mészáros, Tamás AU - Őrfi, Erik AU - Fülöp, Tamás AU - Hennies, Mark AU - Rosivall, László AU - Hamar, Péter AU - Szebeni, János AU - Szénási, Gábor TI - Complement Activation-Related Pathophysiological Changes in Anesthetized Rats: Activator-Dependent Variations of Symptoms and Mediators of Pseudoallergy JF - MOLECULES J2 - MOLECULES VL - 24 PY - 2019 IS - 18 PG - 12 SN - 1420-3049 DO - 10.3390/molecules24183283 UR - https://m2.mtmt.hu/api/publication/30799114 ID - 30799114 N1 - * Megosztott szerzőség AB - Complement (C) activation can underlie the infusion reactions to liposomes and other nanoparticle-based medicines, a hypersensitivity syndrome that can be partially reproduced in animal models. However, the sensitivities and manifestations substantially differ in different species, and C activation may not be the only cause of pathophysiological changes. In order to map the species variation of C-dependent and -independent pseudoallergy (CARPA/CIPA), here we used known C activators and C activator liposomes to compare their acute hemodynamic, hematological, and biochemical effects in rats. These C activators were cobra venom factor (CVF), zymosan, AmBisome (at 2 doses), its amphotericin B-free vehicle (AmBisombo), and a PEGylated cholesterol-containing liposome (PEG-2000-chol), all having different powers to activate C in rat blood. The pathophysiological endpoints measured were blood pressure, leukocyte and platelet counts, and plasma thromboxane B2, while C activation was assessed by C3 consumption using the Pan-Specific C3 assay. The results showed strong linear correlation between C activation and systemic hypotension, pointing to a causal role of C activation in the hemodynamic changes. The observed thrombocytopenia and leukopenia followed by leukocytosis also correlated with C3 conversion in case of C activators, but not necessarily with C activation by liposomes. These findings are consistent with the double hit hypothesis of hypersensitivity reactions (HSRs), inasmuch as strong C activation can fully account for all symptoms of HSRs, but in case of no-, or weak C activators, the pathophysiological response, if any, is likely to involve other activation pathways. LA - English DB - MTMT ER - TY - JOUR AU - Fülöp, Tamás AU - Kozma, Gergely Tibor AU - Vashegyi, Ildikó AU - Mészáros, Tamás AU - Rosivall, László AU - Urbanics, Rudolf AU - Storm, Gert AU - Metselaar, Josbert M. AU - Szebeni, János TI - Liposome-induced hypersensitivity reactions: Risk reduction by design of safe infusion protocols in pigs JF - JOURNAL OF CONTROLLED RELEASE J2 - J CONTROL RELEASE VL - 309 PY - 2019 SP - 333 EP - 338 PG - 6 SN - 0168-3659 DO - 10.1016/j.jconrel.2019.07.005 UR - https://m2.mtmt.hu/api/publication/30786524 ID - 30786524 N1 - Megosztott szerzők: Fülöp T, Kozma G, Vashegyi I, és Meselaar J, Szebeni J AB - Intravenous administration of liposomal drugs can entail infusion reactions, also known as hypersensitivity reactions (HSRs), that can be severe and sometimes life-threatening in a small portion of patients. One empirical approach to prevent these reactions consists of lowering the infusion speed and extending the infusion time of the drug. However, different liposomal drugs have different levels of reactogenicity, which means that the optimal protocol for each liposomal drug may differ and should be identified and evaluated to make the treatment as safe and convenient as possible. The goal of the present study was to explore the use of pigs for that purpose, using PEGylated liposomal prednisolone (PLP) as a model drug. We compared the reactogenicities of bolus versus infusion protocols involving 2-, 3- and 4-step dose escalations for a clinically relevant total dose, also varying the duration of infusions. The strength of the reaction was measured via continuous recording of hemodynamic parameters and blood thromboxane B2 levels. We showed that bolus administration or rapid infusion of PLP caused transient changes in systemic and pulmonary blood pressure and heart rate, most notably pulmonary hypertension with paralleling rises in plasma thromboxane B2. These adverse responses could be significantly reduced or eliminated by slow infusion of PLP, with the 3-h 3-step dose escalation protocol being the least reactogenic. These data suggest that the pig model enables the development of safe infusion protocols for reactogenic nanomedicines. LA - English DB - MTMT ER - TY - JOUR AU - Kozma, Gergely Tibor AU - Mészáros, Tamás AU - Vashegyi, Ildikó AU - Fülöp, Tamás AU - Őrfi, Erik AU - Dézsi, László AU - Rosivall, László AU - Bavli, Yaelle AU - Urbanics, Rudolf AU - Mollnes, Tom Eirik AU - Barenholz, Yechezkel AU - Szebeni, János TI - Pseudo-anaphylaxis to Polyethylene Glycol (PEG)-Coated Liposomes: Roles of Anti-PEG IgM and Complement Activation in a Porcine Model of Human Infusion Reactions JF - ACS NANO J2 - ACS NANO VL - 13 PY - 2019 IS - 8 SP - 9315 EP - 9324 PG - 10 SN - 1936-0851 DO - 10.1021/acsnano.9b03942 UR - https://m2.mtmt.hu/api/publication/30786516 ID - 30786516 N1 - Nanomedicine Research and Education Center, Semmelweis University, Budapest, 1089, Hungary SeroScience Ltd., Budapest, 1125, Hungary Department of Pathophysiology, International Nephrology Research and Training Center, Semmelweis University, Budapest, 1089, Hungary Laboratory of Membrane and Liposome Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, 9112102, Israel Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, 0372, Norway Research Laboratory, Nordland Hospital Bodø, Faculty of Health Sciences and TREC, University of Tromsø, Tromsø, 9019, Norway Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, 7012, Norway Department of Nanobiotechnology and Regenerative Medicine, Faculty of Health, Miskolc University, Miskolc, 3515, Hungary Cited By :114 Export Date: 8 February 2024 Correspondence Address: Szebeni, J.; Nanomedicine Research and Education Center, Hungary; email: jszebeni@seroscience.com LA - English DB - MTMT ER - TY - JOUR AU - Őrfi, Erik AU - Mészáros, Tamás AU - Hennies, Mark AU - Fülöp, Tamás AU - Dézsi, László AU - Nardocci, Alexander AU - Rosivall, László AU - Hamar, Péter AU - Neun, Barry W. AU - Dobrovolskaia, Marina A. AU - Szebeni, János AU - Szénási, Gábor TI - Acute physiological changes caused by complement activators and amphotericin B-containing liposomes in mice JF - INTERNATIONAL JOURNAL OF NANOMEDICINE J2 - INT J NANOMED VL - 14 PY - 2019 SP - 1563 EP - 1573 PG - 11 SN - 1176-9114 DO - 10.2147/IJN.S187139 UR - https://m2.mtmt.hu/api/publication/30466738 ID - 30466738 N1 - * Megosztott szerzőség LA - English DB - MTMT ER - TY - JOUR AU - Fülöp, Tamás AU - Nemes, R AU - Mészáros, Tamás AU - Urbanics, R AU - Kok, RJ AU - Jackman, JA AU - Cho, NJ AU - Storm, G AU - Szebeni, János TI - Complement activation in vitro and reactogenicity of low-molecular weight dextran-coated SPIONs in the pig CARPA model: Correlation with physicochemical features and clinical information JF - JOURNAL OF CONTROLLED RELEASE J2 - J CONTROL RELEASE VL - 270 PY - 2018 SP - 268 EP - 274 PG - 7 SN - 0168-3659 DO - 10.1016/j.jconrel.2017.11.043 UR - https://m2.mtmt.hu/api/publication/3379746 ID - 3379746 N1 - Megosztott szerzők: Fülöp T, Nemes R és Storm G AB - The unique magnetic properties of superparamagnetic iron oxide nanoparticles (SPIONs) have led to their increasing use in drug delivery and imaging applications. Some polymer-coated SPIONs, however, share with many other nanoparticles the potential of causing hypersensitivity reactions (HSRs) known as complement (C) activation-related pseudoallergy (CARPA). In order to explore the roles of iron core composition and particle surface coating in SPION-induced CARPA, we measured C activation by 6 different SPIONs in a human serum that is known to react to nanoparticles (NPs) with strong C activation. Remarkably, only the carbox-ymethyldextran-coated (ferucarbotran, Resosvist (R)) and dextran-coated (ferumoxtran-10, Sinerem (R)) SPIONs caused significant C activation, while the citric acid, phosphatidylcholine, starch and chitosan-coated SPIONs had no such effect. Focusing on Resovist and Sinerem, we found Sinerem to be a stronger activator of C than Resovist, although the individual variation in 15 different human sera was substantial. Further analysis of C activation by Sinerem indicated biphasic dose dependence and significant production of C split product Bb but not C4d, attesting to alternative pathway C activation only at low doses. Consistent with the strong C activation by Sinerem and previous reports of HSRs in man, injection of Sinerem in a pig led to dose-dependent CARPA, while Resovist was reaction-free. Using nanoparticle tracking analysis, it was further determined that Sinerem, more than Resovist, displayed multimodal size distribution and significant fraction of aggregates - factors which are known to promote C activation and CARPA. Taken together, our findings offer physicochemical insight into how key compositional factors and nanoparticle size distribution affect SPION-induced CARPA, a knowledge that could lead to the development of SPIONs with improved safety profiles. LA - English DB - MTMT ER - TY - JOUR AU - Fülöp, Tamás AU - Mészáros, Tamás AU - Kozma, Gergely Tibor AU - Szebeni, János AU - Józsi, Mihály TI - Infusion Reactions Associated with the Medical Application of Monoclonal Antibodies: The Role of Complement Activation and Possibility of Inhibition by Factor H JF - ANTIBODIES J2 - ANTIBODIES VL - 7 PY - 2018 IS - 1 PG - 9 SN - 2073-4468 DO - 10.3390/antib7010014 UR - https://m2.mtmt.hu/api/publication/3362373 ID - 3362373 N1 - Cited By :10 Export Date: 19 October 2023 Correspondence Address: Fülöp, T.; Nanomedicine Research and Education Center, Hungary; email: fulopgyulatamas@gmail.com AB - Human application of monoclonal antibodies (mAbs), enzymes, as well as contrast media and many other particulate drugs and agents referred to as nanomedicines, can initiate pseudoallergic hypersensitivity reactions, also known as infusion reactions. These may in part be mediated by the activation of the complement system, a major humoral defense system of innate immunity. In this review, we provide a brief outline of complement activation-related pseudoallergy (CARPA) in general, and then focus on the reactions caused by mAb therapy. Because the alternative pathway of complement activation may amplify such adverse reactions, we highlight the potential use of complement factor H as an inhibitor of CARPA. LA - English DB - MTMT ER -