Session Speaker
Mechanisms And Approaches For The Prevention Of Adverse Immune Reactions To Nanomedicines
J. Szebeni, P. Bedocs, Z. Rozsnyay, L. Rosivall, M. Tóth and R. Bunger
Hungary

Intravenous administration of particulate drugs and other therapeutic or diagnostic agents whose size in the nanometer range corresponds to that of the smallest pathogens, such as viruses, can trigger an immune reaction typical of acute allergy. The symptoms vary from mild skin and respiratory changes to severe cardiopulmonary distress or even lethal anaphylaxis. These hypersensitivity reactions (HSRs) do not usually involve IgE, and are referred to as pseudoallergy. Many pseudoallergic reactions have been shown to be due to complement (C) activation, rationalizing the distinction of a novel subcategory of type I allergic reactions, called C activation-related pseudoallergy (CARPA). Nevertheless, some nanomedicine-induced reactions involve both IgE and C, representing mixed Type I reaction. Nanoparticle forming medicines causing CARPA include liposomal and micellar drugs (Doxil, Ambisome, Taxol, poloxamer 188 and 407), while one example of a mixed-type reaction is the anaphylaxis caused by i.v. protamine.

The mechanism of C activation by nanomedicines may involve both the classical and the alternative pathways; the former seems to predominate in the case of liposomes, while alternative pathway activation is very expressed with micellar drugs. Coupling of C activation to clinical reaction involves multiple amplification pathways, including C3a and C5a formation, triggering of mast cells, basophils and macrophages for secretion of a range of vasoactive secondary mediators, including histamine, thromboxane and leukotrienes. The latter mediators act via selective receptors on vascular and bronchial endothelial and smooth muscle cells.

There are several approaches for the prevention of nanomedicine-caused HSRs. As for the prediction of reactions, as the most obvious way for their prevention, the standard skin tests and IgE assays identify only the small fraction of IgE co-mediated reactions. Prediction of CARPA has not yet reached standard clinical or laboratory practice, although in vitro ELISA and animal tests are already available to determine which drug in which individual will cause C activation and related HSRs. The most sensitive and predictive assays identified to date measure the formation of the terminal C complex (SC5b-9) in human blood in vitro and the cardiopulmonary changes of pigs or dogs, in vivo, after exposure to the test drugs. Desensitization methods also may work, particularly for IgE-mediated reactions. From among the options of pharmacologic intervention, immunosuppression and C inhibition proved to offer more or less efficacy. Inhibitors of secunder mediator release or action, for example with indomethacin, anti-C5a antibodies or adenosine receptor blockers, proved to be efficient in the porcine model of CARPA.