DEVELOPMENT OF IMMUNOTHERAPY To HEMATOLOGIC MALIGNANCIES

血液系统恶性肿瘤免疫疗法的进展

基本信息

批准号：
13557080
负责人：
CHIBA Shigeru
金额：
$ 8.9万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

We aimed at development of immunotherapy to hematological malignancies using NKT cells. Human NKT cells, ligands for which are CD1d/glycolipid complexes, utilize Va24 in TCR. As in mouse NKT cells, presence of CD4-CD8-and CD4+ subsets have been known in human NKT cells. In this project, we now newly identified the CD8+ subset. Moreover, we clarified the differences in the function among these subsets, particulaily the difference in the cytokine production profile.We here found that human T cell neoplasms frequently express CD1d at a high level and that Va24NKT cells show anti-tumor activity against the CD1d+ T cell neoplastic cells. A glycolipid, a-galactosyl ceramide (a-GalCer), enhanced the anti-tumor activity of NKT cells in vitro. Therefore, direct administration of a-GalCer or administration of NKT cells that are expanded in vitro by a-GalCer could be a potential therapeutic option for T cell neoplastic diseases.To further investigate such a possibility, we established an in vivo model for NKT cell-based anti-tumor therapy. A mouse precursor T cell tumor cell line, EL-4 expresses CD1d only at a weak level. We introduced CD1d cDNA into EL-4 and obtained cell lines overexpressing CD1d at various levels. In vitro, NKT-based cytotoxicity was stronger for EL-4 expressing CD1d at higher levels. Then, these cell lines were injected into syngenic B57BL/6 mice. We found that mice injected with EL-4 lines expressing higher levels of CD1d survived longer periods of time and that the survival time was extended by the administration of a-GalCer. These results indicate that endogenous NKT cells inhibit tumor growth through CD1d interaction.We now creating a protocol on a clinical trial for T cell lymphoblastic leukemia using NKT cells.

我们的目标是开发使用 NKT 细胞治疗血液恶性肿瘤的免疫疗法。人类 NKT 细胞的配体是 CD1d/糖脂复合物，在 TCR 中利用 Va24。与小鼠 NKT 细胞一样，人类 NKT 细胞中也存在 CD4-CD8-和 CD4+ 亚群。在这个项目中，我们现在新鉴定了 CD8+ 子集。此外，我们阐明了这些亚群之间功能的差异，特别是细胞因子产生谱的差异。我们在这里发现人类T细胞肿瘤经常高水平表达CD1d，并且Va24NKT细胞表现出针对CD1d+ T的抗肿瘤活性细胞肿瘤细胞。糖脂、α-半乳糖基神经酰胺 (a-GalCer) 可增强 NKT 细胞的体外抗肿瘤活性。因此，直接施用a-GalCer或施用通过a-GalCer在体外扩增的NKT细胞可能是T细胞肿瘤疾病的潜在治疗选择。为了进一步研究这种可能性，我们建立了NKT细胞的体内模型为主的抗肿瘤治疗。 EL-4 是一种小鼠前体 T 细胞肿瘤细胞系，仅以微弱水平表达 CD1d。我们将CD1d cDNA引入EL-4并获得不同水平过表达CD1d的细胞系。在体外，对于表达 CD1d 水平较高的 EL-4，基于 NKT 的细胞毒性更强。然后，将这些细胞系注射到同源 B57BL/6 小鼠中。我们发现，注射表达较高水平 CD1d 的 EL-4 系的小鼠存活时间更长，并且通过施用 a-GalCer 可以延长存活时间。这些结果表明内源性 NKT 细胞通过 CD1d 相互作用抑制肿瘤生长。我们现在正在制定使用 NKT 细胞治疗 T 细胞淋巴细胞白血病的临床试验方案。