title: PEGylated liposomes elicit an anti-PEG IgM response in a T cell-independent manner.
abstract: We recently reported that intravenous injections of "empty" PEGylated liposomes without encapsulated or surface coupled proteins elicit a PEG-specific IgM response in rats. In the present study, simultaneous weak anti-PEG IgG and strong anti-PEG IgM responses were detected following intravenous injections of "empty" PEGylated liposomes. The pattern of immune response appears to differ from the classic primary response against T cell-dependent (TD) antigens. The anti-PEG IgM response was detected in T-cell deficient nude BALB/c mice following intravenous injection of "empty" PEGylated liposomes, suggesting that "empty" PEGylated liposomes initiate the immune response against PEG in a T cell-independent manner. In vitro splenic lymphocytes-proliferation assay indicated that TNP-LPS, a typical type 1 T cell-independent (TI) antigen (TI-1 antigen), significantly primed the proliferation, while TNP-Ficoll, a typical type 2 TI antigen (TI-2 antigen), and "empty" PEGylated liposomes did not prime any proliferation under these experimental conditions. In addition, in splenic marginal zone (MZ) B-cell-depleted rats, the anti-PEG IgM response was diminished, while the immune reactions against TNP-BSA (a TD antigen) and TNP-LPS (TI-1 antigen) were not diminished. These results demonstrate that "empty" PEGylated liposomes may promote the immune response against PEG as a result of priming the activation of MZ B cells, as TI-2 antigen promotes a specific IgM response. In conclusion, although the mechanistic details behind the immune reaction against "empty" PEGylated liposomes are not yet clear, the liposomes elicit an anti-PEG IgM response in a T cell-independent manner and appear to be a TI-2 antigen, and splenic MZ B cells may be essential for the immune response against "empty" PEGylated liposomes.
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Bioscience, The University of Tokushima, 1-78-1, Sho-machi, Tokushima 770-8505, Japan.
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Ishida
authors.forename: Xinyu
authors.initials: X
authors.lastname: Wang
authors.forename: Taro
authors.initials: T
authors.lastname: Shimizu
authors.forename: Kosuke
authors.initials: K
authors.lastname: Nawata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiwada
mesh_terms: D000818:Animals; D000955:Antigens, T-Independent / Q000276:immunology*; D049109:Cell Proliferation; D003520:Cyclophosphamide / Q000494:pharmacology; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000096:biosynthesis* / Q000097:blood; D007275:Injections, Intravenous; D008081:Liposomes / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011092:Polyethylene Glycols; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
chemical_list: D000955:Antigens, T-Independent; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008081:Liposomes; D011092:Polyethylene Glycols; D003520:Cyclophosphamide