Animal Models of Complement-Mediated Hypersensitivity Reactions to Liposomes and Other Lipid-Based Nanoparticles

Abstract

Intravenous injection of some liposomal drugs, diagnostic agents, micelles and other lipid-based nanoparticles can cause acute hypersensitivity reactions (HSRs) in a high percentage (up to 45%) of patients, with hemodynamic, respiratory and cutaneous manifestations. The phenomenon can be explained with activation of the complement (C) system on the surface of lipid particles, leading to anaphylatoxin (C5a and C3a) liberation and subsequent release reactions of mast cells, basophils and possibly other inflammatory cells in blood. These reactions can be reproduced and studied in pigs, dogs and rats, animal models which differ from each other in sensitivity and spectrum of symptoms. In the most sensitive pig model, a few miligrams of liposome (phospholipid) can cause anaphylactoid shock, characterized by pulmonary hypertension, systemic hypotension, decreased cardiac output and major cardiac arrhythmias. Pigs also display cutaneous symptoms, such as flushing and rash. The sensitivity of dogs to hemodynamic changes is close to that of pigs, but unlike pigs, dogs also react to micellar lipids (such as Cremophor EL) and their response includes pronounced blood cell and vegetative neural changes (e.g., leukopenia followed by leukocytosis, thrombocytopenia, fluid excretions). Rats are relatively insensitive inasmuch as hypotension, their most prominent response to liposomes, is induced only by one or two orders of magnitude higher phospholipid doses (based on body weight) compared to the reactogenic dose in pigs and dogs. It is suggested that the porcine and dog models are applicable for measuring and predicting the (pseudo)allergic activity of particulate "nanodrugs".

Adipose tissue macrophages in non-rodent mammals: a comparative study

“…Obesity causes adipose tissue inflammation in cats ( Van de Velde et al 2013); however, a high-fat diet increases oxidative stress rather than inflammation in the adipose tissue in cats (Verbrugghe et al 2014). In dogs, lipid metabolites and liposomes increase inflammation (Szebeni et al 2007) and weight loss improves the inflammatory state (Bastien et al 2015). These findings suggest that lipid overload shifts ATMs into an inflammatory phenotype and that visceral obesity causes inflammation in dogs.…”

“…Despite obesity being a condition rarely occurring in the majority of mammalian species, adipose tissue is nevertheless of major importance in metabolism and the endocrine system (Szebeni et al 2007). Our comparative study shows that adipose tissue is rich in resident immune cells in mammals and that the interplay between immune cells and adipose cells might be an evolutionary conserved trait.…”

“…We analyze farmed ruminant species, such as cattle (Bos primigenius taurus), domestic goat (Capra aegagrus hircus) and sheep (Ovis aries). In these animals, adipose tissue is important in the determination of meat and milk production and in the maintenance of fertility (Szebeni et al 2007). We also study animals frequently brought to veterinary practices, such as the domestic cat (Felis catus) and the domestic dog (Canis familiaris).…”

Pilot Trial of Intravenous Lipid Emulsion Treatment for Severe Nifedipine-Induced Shock

“…Anaphylactoid reactions have been observed after infusion of specific liposomes and fat-containing nanoparticles [32][33][34]. These so-called CARPA reactions (compliment activation-related pseudoallergy) have been reported in various animal models including dogs, rats, and swine and may result in hypotension, hypertension, tachycardia, bradycardia, flushing, and rash.…”

“…These so-called CARPA reactions (compliment activation-related pseudoallergy) have been reported in various animal models including dogs, rats, and swine and may result in hypotension, hypertension, tachycardia, bradycardia, flushing, and rash. These reactions have been examined in swine exposed to liposomes like doxorubicin hydrochloride liposome injection and liposome-encapsulated hemoglobin as they mimic human reactions to some liposomes and fatcontaining nanoparticles [32]. We cannot completely exclude an effect from CARPA contributing to the demise of our animals at a very vulnerable hemodynamic point in the experiment.…”