title: Anti-PEG IgM and complement system are required for the association of second doses of PEGylated liposomes with splenic marginal zone B cells.
abstract: The accelerated blood clearance (ABC) phenomenon makes it crucial to use PEGylated liposomes and micelles to deliver drugs. The ABC phenomenon is an immune response against an initial dose of PEGylated liposome, which causes subsequent doses to be rapidly cleared by macrophages in the liver. We recently found that in the early phase of the ABC phenomenon, subsequent doses of PEGylated liposomes were associated with splenic marginal zone (MZ)-B cells and were transported from the MZ to the follicle (FO). In this study, we investigated the underlying mechanisms behind the association of subsequent doses of PEGylated liposomes with MZ-B cells in the spleen. Serum factors, anti-PEG IgM and complement system, were crucial to the association of PEGylated liposomes with MZ-B cells, while the sensitization of MZ-B cells by the first dose of PEGylated liposomes was not significant. It was the complement receptors (CRs) on the MZ-B cells, rather than either the PEG-specific B-cell receptors or the IgM Fc receptors, that were the main contributors to the association between PEGylated liposomes and MZ-B cells. It appeared that anti-PEG IgM would bind to PEGylated liposomes and causes subsequent complement activation, resulting in the formation of immune complexes of PEGylated liposome-anti-PEG IgM-complement. The MZ-B cells then recognized these immune complexes via their CRs. Such an association via CRs might have triggered the transport of the immune complex by MZ-B cells to the FO in the spleen. The information obtained in this study might be useful in the development of an efficient antigen delivery system to usher PEGylated nanoparticles into FO dendritic cells.
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Mima
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Hashimoto
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Ukawa
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ando
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiwada
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, Japan. Electronic address: ishida@tokushima-u.ac.jp.
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Ishida
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects* / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology*; D008081:Liposomes / Q000494:pharmacology; D008297:Male; D053758:Nanoparticles; D011092:Polyethylene Glycols / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000276:immunology*
chemical_list: D007075:Immunoglobulin M; D008081:Liposomes; D011092:Polyethylene Glycols; C000595209:polyethylene glycol 1000
keywords: ABC phenomenon; Anti-PEG IgM; Complement system; Marginal zone B cells; PEGylated liposome