B7-CD28/CTLA-4 INTERACTIONS IN IMMUNITY TO TUMORS

B7-CD28/CTLA-4 在肿瘤免疫中的相互作用

• 批准号: 2896285
• 负责人: MARGALIT B MOKYR
• 金额: $ 18.13万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2896285
• 关键词: CD28 molecule; T lymphocyte; cellular immunity; gene expression; immunofluorescence technique; laboratory mouse; melphalan; monoclonal antibody; neoplasm /cancer chemotherapy; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; surface antigens; tissue /cell culture

DESCRIPTION (Adapted from the Investigator's Abstract): Studies are proposed to elucidate the physiological function of the B7/CD28 costimulatory pathway in the acquisition of T-cell-dependent tumor-eradicating immunity by hitherto immunosuppressed mice bearing large tumors and extensive metastases. Particular emphasis will be placed on determining if B7-1 and/or B7-2 up-regulation on host cells or on tumor cells is important for the low-dose melphalan-induced acquisition of tumor eradicating immunity by MOPC-315 tumor bearers. In addition, this study will elucidate the mechanisms through which the low-dose chemotherapy leads to up-regulation of B7-1 and/or B7-2 expression by cells identified as important for the low-dose L-PAM-induced acquisition of tumor-eradicating immunity by the hitherto immunosuppressed MOPC-315 tumor bearers. Studies are also proposed to determine why blockade of the B7/CTLA-4 interaction does not offer any therapeutic benefits to MOPC-315 tumor bearers. Specifically, it will test the hypothesis that the failure of anti-CTLA-4 treatment to offer any therapeutic benefits in the MOPC-315 tumor system, is due to the fact that at the time of anti-CTLA-4 administration, the activated T-cells are not predominantly of the type that is involved in the generation/exertion (rather than inhibition) of tumor-eradicating immunity, and the anti-CTLA-4 treatment prevents the shut-off of the activity of both kinds of activated T-cells. In addition, it will be determined if the beneficial effects of anti-CTLA-4 treatment can be realized in the MOPC-315 tumor system when the balance is shifted through external manipulations, towards activated T-cells that are involved in the generation/exertion of tumor-eradicating immunity. Finally, it will be determined if the principles learned from the MOPC-315 tumor model can be extended to a different tumor model. In summary, the studies proposed will provide valuable information regarding the physiological functions of the B7-Cd28/CTLA-4 costimulatory pathway in vivo in mice bearing a large tumor, both before and after the mice are subjected to therapeutic modalities known to lead to the acquisition of tumor-eradicating immunity by the hitherto immunosuppressed tumor bearers. This information will in turn facilitate the design of rational approaches to manipulate this key immunoregulatory pathway to the benefit of the tumor bearers.

描述（改编自研究者摘要）：研究 提出阐明B7/CD 28的生理功能， T细胞依赖性获得中的共刺激途径 肿瘤根除免疫迄今免疫抑制小鼠携带大 肿瘤和广泛转移。 将特别强调 确定B7-1和/或B7-2是否在宿主细胞或肿瘤上上调 细胞对于低剂量美法仑诱导的肿瘤获得是重要的 消除MOPC-315肿瘤携带者的免疫力。 此外，这项研究 将阐明低剂量化疗导致 上调被鉴定为B7-1和/或B7-2的细胞的表达 对于低剂量L-PAM诱导的肿瘤根除的获得重要 免疫抑制的MOPC-315肿瘤携带者的免疫力。 研究 还提出了确定为什么阻断B7/CTLA-4相互作用 对MOPC-315肿瘤携带者不提供任何治疗益处。 具体地说，它将检验抗CTLA-4的失败 在MOPC-315肿瘤系统中提供任何治疗益处的治疗是 由于在施用抗CTLA-4时， 活化的T细胞并不主要是参与免疫反应的类型。 产生/发挥（而不是抑制）肿瘤根除免疫， 而抗CTLA-4治疗阻止了这两种活性的关闭， 激活的T细胞 此外，还将确定 在MOPC-315中可以实现抗CTLA-4治疗的有益效果 当平衡通过外部操作转移时， 对参与产生/发挥的活化的T细胞 消除肿瘤的免疫力 最后，将确定 从MOPC-315肿瘤模型中学到的原理可以扩展到 不同的肿瘤模型 总之，拟议的研究将提供 有关的生理功能的有价值的信息， B7-Cd 28/CTLA-4共刺激通路在携带大肿瘤的小鼠体内， 在对小鼠进行已知的治疗方式之前和之后 导致迄今为止的免疫系统获得消除肿瘤的免疫力， 免疫抑制的肿瘤携带者。 这些信息将反过来促进 设计合理的方法来操纵这一关键的免疫调节， 这是一条有益于肿瘤携带者的途径。