T cell-independent B cell response is responsible for ABC phenomenon induced by repeated injection of PEGylated liposomes
T cell-independent B cell response is responsible for ABC phenomenon induced by repeated injection of PEGylated liposomes
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DOI：
10.1016/j.ijpharm.2010.03.022
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发表时间：
2010-06-15
影响因子：
5.8
通讯作者：
Oku, Naoto
中科院分区：
文献类型：
--
作者：
Koide, Hiroyuki;Asai, Tomohiro;Oku, Naoto
重复注射聚乙二醇修饰的（PEG化）脂质体会导致它们从血流中快速清除，这种现象称为加速血液清除（ABC）。在本研究中，我们专注于负责ABC现象的免疫系统。将PEG化脂质体预先给予BALB/c小鼠，然后在预给药后3天给予[H-3]标记的脂质体。与我们先前的结果一致，用PEG化脂质体预给药触发[H-3]标记的PEG化脂质体从血流中的快速清除，但用PEG化脂质体包封多柔比星（Dox）则没有。此外，我们发现，ABC现象时，观察到的混合物的自由Dox和PEG化脂质体预给药。这些数据表明，负责ABC现象的免疫细胞可能被包封在PEG化脂质体中的Dox选择性地损伤。在BALB/c nu/nu小鼠中也观察到ABC现象，而在BALB/c SCID小鼠中未观察到。在BALB/c nu/nu小鼠中，由PEG化脂质体刺激诱导的抗PEG IgM抗体的量显著增加，但在BALB/c SCID小鼠中不增加。这些数据表明T细胞非依赖性B细胞应答在ABC现象中起重要作用。此外，本研究表明，聚乙二醇化脂质体可能被识别的B细胞作为胸腺非依赖性2型（TI-2）抗原。本研究为脂质体药物的进一步开发提供了重要信息。(C)2010爱思唯尔有限公司版权所有。
Repeated injection of polyethyleneglycol-modified (PEGylated) liposomes causes a rapid clearance of them from the bloodstream, this phenomenon is called accelerated blood clearance (ABC). In the present study, we focused on the immune system responsible for the ABC phenomenon. PEGylated liposomes were preadministered to BALB/c mice and [H-3]-labeled ones were then administered to them 3 days after the preadministration. Consistent with our previous results, the preadministration with PEGylated liposomes triggered the rapid clearance of [H-3]-labeled PEGylated liposomes from the bloodstream, but that with PEGylated liposomes encapsulating doxorubicin (Dox) did not. In addition, we found that the ABC phenomenon was observed when a mixture of free Dox and PEGylated liposomes was preadministered. These data indicate that immune cells responsible for the ABC phenomenon might be selectively damaged by the Dox encapsulated in PEGylated liposomes. The ABC phenomenon was also observed in BALB/c nu/nu mice, but not in BALB/c SCID mice. The amount of anti-PEG IgM antibody induced by the stimulation with the PEGylated liposomes was significantly increased in the BALB/c nu/nu mice, but not in the BALB/c SCID ones. These data indicate that a T cell-independent B cell response would play a significant role in the ABC phenomenon. Furthermore, the present study suggests that PEGylated liposomes might be recognized by B cells as a thymus-independent type 2 (TI-2) antigen. The present study provides important information for the future development of liposomal medicines. (C) 2010 Elsevier B.V. All rights reserved.