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Development of immunotherapy for brain tumors targeting carbohydrate antigens of glycolipids

针对糖脂糖抗原的脑肿瘤免疫疗法的开发

基本信息

批准号：
05807129
负责人：
IBAYASHI Yukihiro
金额：
$ 1.02万
依托单位：
Sapporo Medical University School of Midicine, Department of Neurosurgery
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1994
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05807129/
关键词：
glioma immunotherapy GM3 GM2 TLC cell cycle brain tumor LAK cells ganglioside

项目摘要

The main objective of this project is to develop a novel immunotherapy for gliomas, in which glycolipid antigens are analyzed and quantified systematically and a set of appropriate antibodies would be selected according to the antigenic profile of an individual glioma. We first analyzed glycosphingolipid composition of 11 human glioma cell line, one melanoma cell line, and one fibroblast cell line. The glycosphingolipid composition of glioma cell line are different from that of normal nerve cell. We also found that a human glioma cell line U118MG could modulate glycosphingolipid expression via certain cytodines. We next analyzed the glycolipid antigens of 10 human gliomas, which were revealed to consist mainly of GM3 and GM2 . The reactivity of monoclonal antibodies against those gangliosides was examined next either as chemically isolated antigens or cell surface ones. The intensity of antibody binding was dose-dependent as the gangliosides were prepared on a thin-layr chromatographic plate, On the contrary, antibody reaction was more complex on the cell surface ; GM3 showed positive and negative threshould of antibody binding, and GM2 gave stronger reaction when GM3 co-existed nearly equally on the cell surface. We next analyzed cellcycle related glycolipids expression on a certain glioma. It was revealed that the total glycolipids were expressed nearly twice during mitosis, and nLc4Cer was significantly enhanced during that phase. The results may suggest better antibody react ions against the mitotic cells. In another experiment, we have found that the cell dendity greatly affects the level of antibody binding against GM3. There should be a variety of factors that influence the antibody reactions against glycolipid antigens. We are now focusing on the glycolipid analysis of surgical specimens of glioma tissue as well as on the factors participating in the antibody reactivity against those antigens.

该项目的主要目标是开发一种新型的神经胶质瘤免疫疗法，其中对糖脂抗原进行系统分析和定量，并根据单个神经胶质瘤的抗原谱选择一组合适的抗体。我们首先分析了 11 种人胶质瘤细胞系、一种黑色素瘤细胞系和一种成纤维细胞系的鞘糖脂组成。神经胶质瘤细胞系的鞘糖脂组成与正常神经细胞不同。我们还发现人胶质瘤细胞系 U118MG 可以通过某些胞嘧啶调节鞘糖脂的表达。接下来，我们分析了 10 种人类神经胶质瘤的糖脂抗原，发现这些抗原主要由 GM3 和 GM2 组成。接下来检查单克隆抗体针对这些神经节苷脂的反应性，或者作为化学分离的抗原，或者作为细胞表面抗原。由于神经节苷脂是在薄层层析板上制备的，因此抗体结合的强度呈剂量依赖性，相反，抗体在细胞表面的反应更为复杂； GM3表现出抗体结合的正阈值和负阈值，当GM3几乎均等地共存于细胞表面时，GM2给出更强的反应。接下来我们分析了某种神经胶质瘤上细胞周期相关糖脂的表达。结果表明，总糖脂在有丝分裂过程中表达了近两次，并且 nLc4Cer 在该阶段显着增强。结果可能表明抗体对有丝分裂细胞有更好的反应。在另一个实验中，我们发现细胞密度极大地影响针对GM3的抗体结合水平。影响针对糖脂抗原的抗体反应的因素应该有多种。我们现在专注于神经胶质瘤组织手术标本的糖脂分析以及参与针对这些抗原的抗体反应性的因素。