Analysis of Anti41BB Mediated Tumor Immunity

Anti41BB介导的肿瘤免疫分析

• 批准号: 6847814
• 负责人: ROBERT S MITTLER
• 金额: $ 28.48万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6847814
• 关键词: Lentivirus; antitumor antibody; biological signal transduction; cytotoxic T lymphocyte; laboratory mouse; minimal residual disease; monoclonal antibody; mutant; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; nonhuman therapy evaluation; protein structure function; transfection /expression vector

DESCRIPTION (provided by the applicant): TCR recognition of antigen + MHC (signal 1) and T cell costimulation (signal 2) are essential for full T cell activation, differentiation, and survival. The prototypical T cell costimulatory receptor, CD28, is a constitutively expressed type I integral transmembrane protein displayed on naive CD4+ and CD8+ T cells. Following the identification of CD28 as a costimulatory receptor, a number of inducible receptors having similar function have been identified. Several of these receptor molecules, including 4-1BB receptors, are members of the tumor necrosis factor receptor (TNFR) superfamily. During the past 5 years our laboratory has been studying the costimulatory activity of 4-1BB receptors in T cell activation. During this period, we have characterized 4-1BB mediated signaling in T cell proliferation, 4-IBB mediated inhibition of T-dependent humoral immunity, its enhancement of CTL-mediated anti-tumor immunity, CU mediated anti-viral immunity; and T cell survival against apoptosis (AICD). The current application seeks to extend our earlier studies in defining potential clinical applications of anti-4-IBB mAbs for treating post-surgical metastatic cancer and to define structure/function relationships that enable 4-1BB receptors to mediate T cell immune responses. To accomplish these objectives the following specific aims will be pursued: (1) establish the optimal conditions for generating anti-4-IBB mAb mediated protective anti-tumor immunity against minimal residual disease, (2) determine whether 4-1BB mediated inhibition of T-dependent humoral immunity is essential for its ability to induce CU mediated anti-tumor immunity, (3) define structure/function relationships in 4-1BB receptor-mediated signal transduction and T cell effector function in establishing anti-tumor immunity through the use of lentiviral reconstitution approaches to express full-length 4-1BB wild type or cytoplasmic point or deletion mutants in mice that are deficient in 4-IBB expression.

描述（申请人提供）：TCR识别抗原+MHC （信号 1）和 T 细胞共刺激（信号 2）对于完整的 T 细胞至关重要 激活、分化和存活。原型T细胞 共刺激受体 CD28 是一种组成型表达的 I 型整合体 跨膜蛋白展示在初始 CD4+ 和 CD8+ T 细胞上。继 CD28 被鉴定为共刺激受体，许多诱导型受体 已鉴定出具有相似功能的受体。其中几个 受体分子，包括4-1BB受体，是肿瘤的成员 坏死因子受体（TNFR）超家族。在过去的5年里我们 实验室一直在研究T细胞中4-1BB受体的共刺激活性 细胞激活。在此期间，我们表征了 4-1BB 介导的 T 细胞增殖中的信号传导，4-IBB 介导的 T 依赖性抑制 体液免疫，其增强CTL介导的抗肿瘤免疫，CU 介导的抗病毒免疫；和 T 细胞抗凋亡存活 (AICD)。 当前的应用程序旨在扩展我们在定义方面的早期研究 抗 4-IBB 单克隆抗体在术后治疗中的潜在临床应用 转移性癌症并定义结构/功能关系，使 4-1BB 受体介导 T 细胞免疫反应。为了完成这些 目标 将追求以下具体目标： (1) 建立 产生抗 4-IBB mAb 介导的保护性抗肿瘤的最佳条件 针对微小残留病的免疫力，（2）确定4-1BB是否介导 抑制 T 依赖性体液免疫对于其能够发挥作用至关重要 诱导 CU 介导的抗肿瘤免疫，(3) 定义结构/功能 4-1BB受体介导的信号转导与T细胞的关系 通过使用建立抗肿瘤免疫的效应器功能 慢病毒重组方法表达全长 4-1BB 野生型或 缺乏 4-IBB 的小鼠中的细胞质点或缺失突变体 表达。