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dc.contributor.authorKozma, Gergely Tibor
dc.contributor.authorMészáros, Támas
dc.contributor.authorVashegyi, Ildikó
dc.contributor.authorFülöp, Tamás Gábor
dc.contributor.authorÖrfi, Erik
dc.contributor.authorDézsi, László
dc.contributor.authorRosivall, László
dc.contributor.authorBavli, Yaelle
dc.contributor.authorUrbanics, Rudolf
dc.contributor.authorMollnes, Tom Eirik
dc.contributor.authorBarenholz, Yechezkel
dc.contributor.authorSzebeni, János
dc.date.accessioned2020-03-10T13:39:31Z
dc.date.available2020-03-10T13:39:31Z
dc.date.issued2019-07-26
dc.description.abstractPolyethylene glycol (PEG)-coated nanopharmaceuticals can cause mild to severe hypersensitivity reactions (HSRs), which can occasionally be life threatening or even lethal. The phenomenon represents an unsolved immune barrier to the use of these drugs, yet its mechanism is poorly understood. This study showed that a single i.v. injection in pigs of a low dose of PEGylated liposomes (Doxebo) induced a massive rise of anti-PEG IgM in blood, peaking at days 7–9 and declining over 6 weeks. Bolus injections of PEG-liposomes during seroconversion resulted in anaphylactoid shock (pseudo-anaphylaxis) within 2–3 min, although similar treatments of naı̈ve animals led to only mild hemodynamic disturbance. Parallel measurement of pulmonary arterial pressure (PAP) and sC5b-9 in blood, taken as measures of HSR and complement activation, respectively, showed a concordant rise of the two variables within 3 min and a decline within 15 min, suggesting a causal relationship between complement activation and pulmonary hypertension. We also observed a rapid decline of anti-PEG IgM in the blood within minutes, increased binding of PEGylated liposomes to IgM+ B cells in the spleen of immunized animals compared to control, and increased C3 conversion by PEGylated liposomes in the serum of immunized pigs. These observations taken together suggest rapid binding of anti-PEG IgM to PEGylated liposomes, leading to complement activation <i>via</i> the classical pathway, entailing anaphylactoid shock and accelerated blood clearance of liposome–IgM complexes. These data suggest that complement activation plays a causal role in severe HSRs to PEGylated nanomedicines and that pigs can be used as a hazard identification model to assess the risk of HSRs in preclinical safety studies.en_US
dc.identifier.citationKozma, Mészáros, Vashegyi, Fülöp TG, Örfi, Dézsi, Rosivall, Bavli, Urbanics R, Mollnes TE, Barenholz, Szebeni. Pseudo-anaphylaxis to polyethylene glycol (PEG)-coated liposomes: Roles of anti-PEG IgM and complement activation in a porcine model of human infusion reactions. ACS Nano. 2019;13(8):9315-9324en_US
dc.identifier.cristinIDFRIDAID 1738743
dc.identifier.doi10.1021/acsnano.9b03942
dc.identifier.issn1936-0851
dc.identifier.issn1936-086X
dc.identifier.urihttps://hdl.handle.net/10037/17709
dc.language.isoengen_US
dc.publisherAmerican Chemical Societyen_US
dc.relation.journalACS Nano
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7-NMP/309820/EU/Nanomedicine for target-specific imaging and treatment of atherosclerosis: development and initial clinical feasibility/NANOATHERO/en_US
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7-HEALTH/602923/EU/Microbubble driven multimodal imaging and theranostics for gliomas/THERAGLIO/en_US
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7-HEALTH/602699/EU/Disarming the intravascular innate immune response to improve treatment modalities for chronic kidney disease/DIREKT/en_US
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright 2019 The Author(s)en_US
dc.subjectVDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710en_US
dc.subjectVDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710en_US
dc.titlePseudo-anaphylaxis to polyethylene glycol (PEG)-coated liposomes: Roles of anti-PEG IgM and complement activation in a porcine model of human infusion reactionsen_US
dc.type.versionpublishedVersionen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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