Ishida Tatsuhiro, Wang Xinyu, Shimizu Taro, Nawata Kosuke, Kiwada Hiroshi
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.
J Control Release. 2007 Oct 8;122(3):349-55. doi: 10.1016/j.jconrel.2007.05.015. Epub 2007 May 21.
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.
我们最近报道，静脉注射未包封或表面偶联蛋白质的“空”聚乙二醇化脂质体可在大鼠中引发聚乙二醇特异性IgM反应。在本研究中，静脉注射“空”聚乙二醇化脂质体后，检测到同时出现微弱的抗聚乙二醇IgG反应和强烈的抗聚乙二醇IgM反应。免疫反应模式似乎不同于针对T细胞依赖性（TD）抗原的经典初次反应。静脉注射“空”聚乙二醇化脂质体后，在T细胞缺陷的裸BALB/c小鼠中检测到抗聚乙二醇IgM反应，这表明“空”聚乙二醇化脂质体以T细胞非依赖性方式引发针对聚乙二醇的免疫反应。体外脾淋巴细胞增殖试验表明，典型的1型T细胞非依赖性（TI）抗原（TI-1抗原）TNP-LPS可显著引发增殖，而典型的2型TI抗原（TI-2抗原）TNP-Ficoll和“空”聚乙二醇化脂质体在这些实验条件下未引发任何增殖。此外，在脾边缘区（MZ）B细胞耗竭的大鼠中，抗聚乙二醇IgM反应减弱，而针对TNP-BSA（TD抗原）和TNP-LPS（TI-1抗原）的免疫反应未减弱。这些结果表明，“空”聚乙二醇化脂质体可能通过引发MZ B细胞的活化来促进针对聚乙二醇的免疫反应，正如TI-2抗原促进特异性IgM反应一样。总之，尽管针对“空”聚乙二醇化脂质体的免疫反应背后的机制细节尚不清楚，但脂质体以T细胞非依赖性方式引发抗聚乙二醇IgM反应，似乎是一种TI-2抗原，脾MZ B细胞可能是针对“空”聚乙二醇化脂质体免疫反应所必需的。
