Investigation into regulation of immune responses by NK cells and NKT cells

NK 细胞和 NKT 细胞对免疫反应调节的研究

基本信息

批准号：
16590411
负责人：
TAKEDA Kazuyoshi
金额：
$ 2.24万
依托单位：
JUNTENDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590411/
关键词：
NK cell NKT cell TRAIL DR5 ICOS CD94 NKG2 TWEAK IFN-γ BCG マクロファージ perforin 分化抗体療法

项目摘要

I have been analyzed target-recognizing and cytotoxic mechanisms of NK cells and NKT cells to elucidate the possibility to regulate immune responses by these cells and/or their functional molecules.1. TNF-related apoptosis-inducing ligand (TRAIL) is the critical cytotoxic molecule of immature NK cells, and which play critical roles in self-defense of infant mice. We also demonstrated that TRAIL-expressing NK cells in the liver of adult mice are immature NK cells potentially developing into mature NK cells.2. TRAIL is a critical molecule in NK cell mediated tumor surveillance. To utilize TRAIL to tumor therapy, we newly established agonistic monoclonal antibody to DR5 (death-inducing TRAIL receptor) (MD5-1). Treatment with MD5-1 induces tumor rejection of TRAIL-sensitive tumor cells by apoptosis induction, and also induces tumor specific T cell responses, and which results in the rejection of TRAIL-resistant tumor variants.3. We demonstrated that IOCS play a role as costimulatory molecules in NKT cell activation, which augments cytokines production and cytotoxic activity.4. Specific ligand-activated NKT cells temporally internalize inhibitory NK cell receptor (CD94/NKG2), and these NKT cells demonstrate dramatically augmented cytokines production and anti-tumor effects when re-stimulated with α-Galactosylceramide (NKT cell specific ligand). We also demonstrated that this regulation is mediated by IFN-γ. These results suggested that combined therapy of NKT cell specific ligand and/or inhibition of NK cell receptor-mediated signal augments NKT cell mediated anti-tumor effects.5. We reported that TRAIL is expressed on tumor infiltrating T cells in BCG-treated bladder cancers in human, and suggested the possible contribution of TRAIL to therapeutic effect of BCG therapy.6. TWEAK, one of the member of TNF super family as TRAIL, is expressed on macrophages and plays important roles in inhibition of tumor growth and immunological tumor surveillance.

我分析了NK细胞和NKT细胞的靶标识别和细胞毒性机制，以阐明这些细胞和/或其功能分子调节免疫反应的可能性。1．TNF相关的凋亡诱导配体（TRAIL）是关键的细胞毒性。我们还证明，成年小鼠肝脏中表达 TRAIL 的 NK 细胞是未成熟的 NK 细胞，有可能发育成成熟的 NK 细胞。 NK细胞。2. TRAIL是NK细胞介导的肿瘤监测的关键分子为了利用TRAIL进行肿瘤治疗，我们新建立了针对DR5（死亡诱导TRAIL受体）的激动性单克隆抗体（MD5-1治疗）。通过诱导凋亡诱导TRAIL敏感肿瘤细胞的肿瘤排斥，并且还诱导肿瘤特异性T细胞反应，从而导致TRAIL抗性肿瘤变体的排斥。3。 IOCS 在 NKT 细胞激活中发挥共刺激分子的作用，增强细胞因子的产生和细胞毒性活性。 4. 特定配体激活的 NKT 细胞暂时内化抑制性 NK 细胞受体 (CD94/NKG2)，并且这些 NKT 细胞表现出显着增强的细胞因子产生和细胞毒性。当用 α-半乳糖神经酰胺（NKT 细胞特异性配体）重新刺激时，我们还证明了这种调节是由 IFN-γ 介导的。建议联合治疗 NKT 细胞特异性配体和/或抑制 NK 细胞受体介导的信号可增强 NKT 细胞介导的抗肿瘤作用。5。我们报道了 TRAIL 在 BCG 治疗的人类膀胱癌的肿瘤浸润 T 细胞上表达。并提示TRAIL对BCG治疗效果的可能贡献。 6．TWEAK是TNF超家族成员之一，表达于巨噬细胞，在抑制肿瘤生长中发挥重要作用。和免疫学肿瘤监测。