@article{MTMT:34754128,
	title = {mRNA-LNP COVID-19 Vaccine Lipids Induce Complement Activation and Production of Proinflammatory Cytokines: Mechanisms, Effects of Complement Inhibitors, and Relevance to Adverse Reactions},
	url = {https://m2.mtmt.hu/api/publication/34754128},
	author = {Bakos, Tamás and Mészáros, Tamás and Kozma, Gergely Tibor and Berényi, Petra and Facskó, Réka and Farkas, Henriette and Dézsi, László and Heirman, Carlo and de Koker, Stefaan and Schiffelers, Raymond and Glatter, Kathryn Anne and Radovits, Tamás and Szénási, Gábor and Szebeni, János},
	doi = {10.3390/ijms25073595},
	journal-iso = {INT J MOL SCI},
	journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES},
	volume = {25},
	unique-id = {34754128},
	issn = {1661-6596},
	abstract = {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.},
	year = {2024},
	eissn = {1422-0067},
	orcid-numbers = {Bakos, Tamás/0000-0002-0569-8343; Facskó, Réka/0000-0002-5611-0597; Farkas, Henriette/0000-0003-2929-1721; Dézsi, László/0000-0002-4190-9793; Szénási, Gábor/0000-0002-7350-6091}
}

@article{MTMT:34571861,
	title = {Complement-mediated dialysis reaction during regular hemodialysis treatment: a case report},
	url = {https://m2.mtmt.hu/api/publication/34571861},
	author = {Pethő, Ákos and Schnabel, Karolina Kornélia and Dézsi, László},
	doi = {10.1186/s13256-024-04365-x},
	journal-iso = {J MED CASE REP},
	journal = {JOURNAL OF MEDICAL CASE REPORTS},
	volume = {18},
	unique-id = {34571861},
	year = {2024},
	eissn = {1752-1947},
	orcid-numbers = {Pethő, Ákos/0000-0001-9776-9841; Dézsi, László/0000-0002-4190-9793}
}

@misc{MTMT:34521339,
	title = {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},
	url = {https://m2.mtmt.hu/api/publication/34521339},
	author = {Bakos, Tamás and Mészáros, Tamás and Kozma, Gergely Tibor and Petra, Berényi and Facskó, Réka and Henriette, Farkas and Dézsi, László and Carlo, Heirman and Stefaan, de Koker and Raymond, Schiffelers and Kathryn, Anne Glatter and Radovits, Tamás and Szénási, Gábor and Szebeni, János},
	unique-id = {34521339},
	abstract = {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.},
	year = {2024},
	pages = {&},
	orcid-numbers = {Bakos, Tamás/0000-0002-0569-8343; Facskó, Réka/0000-0002-5611-0597; Dézsi, László/0000-0002-4190-9793; Szénási, Gábor/0000-0002-7350-6091}
}

@misc{MTMT:34747635,
	title = {COMPARISON OF LIPOSOMAL DRUG-INDUCED BLOOD PRESSURE CHANGES IN MICE AND RATS},
	url = {https://m2.mtmt.hu/api/publication/34747635},
	author = {Szénási, Gábor and Bakos, Tamás and Őrfi, Erik and Mészáros, Tamás and Hricisák, László and Rosivall, László and Hamar, Péter and Benyó, Zoltán and Szebeni, János and Dézsi, László},
	unique-id = {34747635},
	abstract = {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.},
	year = {2023},
	pages = {73-73},
	orcid-numbers = {Szénási, Gábor/0000-0002-7350-6091; Bakos, Tamás/0000-0002-0569-8343; Őrfi, Erik/0000-0002-2190-0708; Hricisák, László/0000-0001-8320-2166; Rosivall, László/0000-0002-9809-3879; Hamar, Péter/0000-0002-1095-3564; Benyó, Zoltán/0000-0001-6015-0359; Dézsi, László/0000-0002-4190-9793}
}

@article{MTMT:33856424,
	title = {Comparative in vitro and in vivo Evaluation of Different Iron Oxide-Based Contrast Agents to Promote Clinical Translation in Compliance with Patient Safety},
	url = {https://m2.mtmt.hu/api/publication/33856424},
	author = {Unterweger, Harald and Janko, Christina and Folk, Tamara and Cicha, Iwona and Stelczerné Kovács, Noémi and Gyebnár, Gyula and Horváth, Ildikó and Máthé, Domokos and Zheng, Kang H. and Coolen, Bram F. and Stroes, Erik and Szebeni, János and Alexiou, Christoph and Dézsi, László and Lyer, Stefan},
	doi = {10.2147/IJN.S402320},
	journal-iso = {INT J NANOMED},
	journal = {INTERNATIONAL JOURNAL OF NANOMEDICINE},
	volume = {18},
	unique-id = {33856424},
	issn = {1176-9114},
	abstract = {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.},
	keywords = {COMPLEMENT ACTIVATION; Magnetic Resonance Imaging; NANOPARTICLES; MRI; CARPA; Nanomedicine},
	year = {2023},
	eissn = {1178-2013},
	pages = {2071-2086},
	orcid-numbers = {Unterweger, Harald/0000-0002-8335-0692; Janko, Christina/0000-0001-5705-6329; Cicha, Iwona/0000-0002-7399-5307; Dézsi, László/0000-0002-4190-9793}
}

@article{MTMT:33022184,
	title = {The Hypertensive Effect of Amphotericin B-Containing Liposomes (Abelcet) in Mice: Dissecting the Roles of C3a and C5a Anaphylatoxins, Macrophages and Thromboxane},
	url = {https://m2.mtmt.hu/api/publication/33022184},
	author = {Őrfi, Erik and Hricisák, László and Dézsi, László and Hamar, Péter and Benyó, Zoltán and Szebeni, János and Szénási, Gábor},
	doi = {10.3390/biomedicines10071764},
	journal-iso = {BIOMEDICINES},
	journal = {BIOMEDICINES},
	volume = {10},
	unique-id = {33022184},
	year = {2022},
	eissn = {2227-9059},
	orcid-numbers = {Őrfi, Erik/0000-0002-2190-0708; Hricisák, László/0000-0001-8320-2166; Dézsi, László/0000-0002-4190-9793; Hamar, Péter/0000-0002-1095-3564; Benyó, Zoltán/0000-0001-6015-0359; Szénási, Gábor/0000-0002-7350-6091}
}

@article{MTMT:32666145,
	title = {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},
	url = {https://m2.mtmt.hu/api/publication/32666145},
	author = {Dézsi, László and Mészáros, Tamás and Kozma, Gergely Tibor and H-Velkei, Mária and Oláh, Csaba Zsolt and Szabó, Miklós and Patkó, Zsófia Panna and Fülöp, Tamás and Hennies, Mark and Szebeni, Miklós and Barta, Bálint András and Merkely, Béla Péter and Radovits, Tamás and Szebeni, János},
	doi = {10.1007/s11357-021-00495-y},
	journal-iso = {GEROSCIENCE},
	journal = {GEROSCIENCE: OFFICIAL JOURNAL OF THE AMERICAN AGING ASSOCIATION (AGE)},
	volume = {44},
	unique-id = {32666145},
	issn = {2509-2715},
	abstract = {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.},
	year = {2022},
	eissn = {2509-2723},
	pages = {597-618},
	orcid-numbers = {Dézsi, László/0000-0002-4190-9793; Fülöp, Tamás/0000-0003-2889-1370; Merkely, Béla Péter/0000-0001-6514-0723}
}

@article{MTMT:32532068,
	title = {A porcine model of hemodialyzer reactions: roles of complement activation and rinsing back of extracorporeal blood},
	url = {https://m2.mtmt.hu/api/publication/32532068},
	author = {Pethő, Ákos and Piecha, Dorothea and Mészáros, Tamás and Urbanics, Rudolf and Moore, Christoph and Canaud, Bernard and Rosivall, László and Mollnes, Tom Eirik and Steppan, Sonja and Szénási, Gábor and Szebeni, János and Dézsi, László},
	doi = {10.1080/0886022X.2021.2007127},
	journal-iso = {RENAL FAILURE},
	journal = {RENAL FAILURE},
	volume = {43},
	unique-id = {32532068},
	issn = {0886-022X},
	year = {2021},
	eissn = {1525-6049},
	pages = {1609-1620},
	orcid-numbers = {Pethő, Ákos/0000-0001-9776-9841; Rosivall, László/0000-0002-9809-3879; Mollnes, Tom Eirik/0000-0002-5785-802X; Szénási, Gábor/0000-0002-7350-6091; Dézsi, László/0000-0002-4190-9793}
}

@article{MTMT:32509180,
	title = {Complement Activation-Related Pseudoallergy (CARPA) in Rats; The Example of Liposomal Amphotericin-B (AmBisome)},
	url = {https://m2.mtmt.hu/api/publication/32509180},
	author = {Bakos, Tamás and Őrfi, Erik and Mészáros, Tamás and Milosevits, Gergely and Csukás, Domokos and Rosivall, László and Hamar, Péter and Dézsi, László and Szebeni, János and Szénási, Gábor},
	journal-iso = {ACTA PHARM HUNG},
	journal = {ACTA PHARMACEUTICA HUNGARICA},
	volume = {91},
	unique-id = {32509180},
	issn = {0001-6659},
	year = {2021},
	eissn = {1587-1495},
	pages = {175-176},
	orcid-numbers = {Bakos, Tamás/0000-0002-0569-8343; Őrfi, Erik/0000-0002-2190-0708; Milosevits, Gergely/0000-0002-5897-9472; Rosivall, László/0000-0002-9809-3879; Hamar, Péter/0000-0002-1095-3564; Dézsi, László/0000-0002-4190-9793; Szénási, Gábor/0000-0002-7350-6091}
}

@article{MTMT:31864261,
	title = {Complement-mediated hypersensitivity reactions to an amphotericin B-containing lipid complex (Abelcet) in pediatric patients and anesthetized rats: Benefits of slow infusion},
	url = {https://m2.mtmt.hu/api/publication/31864261},
	author = {Milosevits, Gergely and Mészáros, Tamás and Őrfi, Erik and Bakos, Tamás and Garami, Miklós and Kovács, Gábor and Dézsi, László and Hamar, Péter and Győrffy, Balázs and Szabó, András and Szénási, Gábor and Szebeni, János},
	doi = {10.1016/j.nano.2021.102366},
	journal-iso = {NANOMED: NANOTECHNOL},
	journal = {NANOMEDICINE: NANOTECHNOLOGY BIOLOGY AND MEDICINE},
	volume = {34},
	unique-id = {31864261},
	issn = {1549-9634},
	year = {2021},
	eissn = {1549-9642},
	orcid-numbers = {Milosevits, Gergely/0000-0002-5897-9472; Őrfi, Erik/0000-0002-2190-0708; Bakos, Tamás/0000-0002-0569-8343; Garami, Miklós/0000-0003-4298-2746; Kovács, Gábor/0000-0001-9924-1645; Dézsi, László/0000-0002-4190-9793; Hamar, Péter/0000-0002-1095-3564; Győrffy, Balázs/0000-0002-5772-3766; Szabó, András/0000-0001-8320-4946; Szénási, Gábor/0000-0002-7350-6091}
}